HX641 37643 
RC857  .Op3  Disease  of  the  pancr 


RECAP 


puiluniyjiiHiuK 


ColumiJia  BBnibergitp 
in  tfje  Citp  of  ^eto  gorfe 

College  of  S^piitiani  anb  ^urseonss 


l^epartment  of  ^tP^iologp 


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in  2010  witii  funding  from 

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http://www.archive.org/details/diseaseofpancrea1903opie 


DISEASE 


OF 


THE    PANCREAS 


ITS    CAUSE    AND    NATURE 


BY 

EUGENE  L.  OPIE,  M.D. 

ASSOCIATE    IN    PATHOLOGY    IN    THE   JOHNS    HOPKINS    UNIVERSITY 

FELLOW   OF   THE   ROCKEFELLER    INSTITUTE 

OF   MEDICAL   RESEARCH 


PHILADELPHIA  AND   LONDON 

J.    B.    LIPPING  OTT    COMPANY 
1903 


Copyright,  1903 

BY 

J.  B.  LiPPiNCOTT  Company 


INTED    BY    J.    B.   LIPPINCOTT    COMPANY,   PHILADELPHIA,    U.S.A. 


2Detiicateti 
oBratituDe  anti  Affection 

to 

William  1$.  Wtltl^ 


PREFACE. 


Seldom  does  the  preface  to  a  treatise  upon  diseases 
of  the  pancreas  fail  to  emphasize  the  obscurity  of 
present  knowledge  concerning  its  subject.  The  ex- 
aggerated statements  regarding  the  infrequency  of 
pathological  changes  affecting  the  organ  may  in  part 
explain  this  deficiency.  Doubtless  the  gland  is  less 
commonly  the  seat  of  generalized  conditions,  such  as 
amyloid  degeneration,  syphilis,  and  tuberculosis,  than 
are  the  liver  and  the  kidneys,  while  acute  and  chronic 
inflammation  less  frequently  attack  it.  Pathological 
conditions  readily  recognized  in  other  organs  may  here, 
owing  to  the  color  and  consistence  of  the  tissue,  be 
overlooked  ;  hence  parenchymatous  and  fatty  degenera- 
tion are  observable  only  when  far  advanced,  miliary  tu- 
bercles are  seen  with  difficulty  and  acute  or  chronic 
inflammation  may  produce  only  slight  macroscopic 
changes.  Moreover,  rapid  self-digestion  and  putrefac- 
tion, to  which  the  gland  is  subject,  not  infrequently 
obscure  the  histological  as  well  as  the  gross  character- 
istics of  otherwise  conspicuous  alterations.  In  view  of 
such  facts  and  the  slight  clinical  significance  usually 
attributed  to  lesions  of  the  organ,   scant  space  is  de- 

S 


6  PREFACE. 

voted  to  diseases  of  the  pancreas  in  text-books  both  of 
medicine  and  of  pathology. 

To  uncertainty  concerning  the  structure  and  functions 
of  the  normal  gland  is  due  in  great  part  ignorance  of 
its  pathology.  The  importance  of  the  pancreatic  juice 
to  intestinal  digestion  has  long  been  recognized,  and 
facts  concerning  this  external  secretion  have  received 
adequate  elucidation.  Heidenhain's  studies  have 
shown  what  changes  occur  in  the  glandular  cells  during 
the  elaboration  of  the  pancreatic  ferments  and  have, 
indeed,  paved  the  way  for  an  understanding  of  the 
processes  of  secretion  in  general.  But  in  addition  to 
the  secreting  cells  there  occur  in  the  pancreas  peculiar 
morphological  elements  which  find  little  analogy  in 
other  glands.  In  1869  Langerhans  pointed  out  certain 
features  which  serve  to  distinguish  the  so-called  salivary 
^land  of  the  abdomen  from  all  other  glandular  organs. 
Within  the  lumen  of  the  acini  he  found  cells  differing 
in  character  from  those  which  secrete  the  pancreatic 
juice,  while  even  more  remarkable  is  the  presence 
throughout  the  parenchyma  of  isolated  bodies  composed 
of  cells  having  no  relation  to  the  ducts  of  the  gland  but 
in  intimate  contact  with  a  rich  vascular  supply.  The 
very  nature  of  the  cells  which  compose  these  bodies 
has  been  disputed,  some  maintaining  that  they  have  a 
common  epithelial  origin  with  the  secreting  cells,  others 
claiming  that  they  bear  a  close  relationship  to  cells  of 
connective  tissue  or  of  lymph  follicles.     The  function 


PREFACE.  7 

of  bodies  of  which  the  structure  is  so  little  understood 
has,  as  might  be  expected,  remained  dubious. 

Our  appreciation  of  the  physiological  and  consequent 
pathological  importance  of  the  pancreas  has  been  greatly 
augmented  by  observations  which  have  demonstrated  its 
relationship  to  carbohydrate  metabolism.  Clinical  ob- 
servations pointed  the  way  to  the  epoch-making  experi- 
ments of  von  Merino-  and  Minkowski,  who  showed  that, 
in  the  absence  of  the  pancreas,  sugar  no  longer  under- 
goes normal  assimilation,  and  that  in  animals  a  condition 
closely  resembling  diabetes  mellitus  results.  The  in- 
fluence which  the  gland  exerts  upon  assimilation  of 
sugar  is  independent  of  the  elaboration  of  the  pancre- 
atic juice,  and  since  it  is  believed  to  act  through  the 
medium  of  the  circulation,  a  hypothetical  internal  se- 
cretion has  been  distinguished  from  the  external  secre- 
tion, the  pancreatic  juice.  The  relation  of  the  disease 
of  carbohydrate  metabolism,  diabetes  mellitus,  to  the 
lesions  of  the  pancreas  which  frequently  accompany 
it  has  been  the  subject  of  much  study,  and  since  all 
lesions  of  the  pancreas  are  not  accompanied  by  dia- 
betes, it  has  remained  to  determine  the  peculiarities  of 
those  lesions  which  are  associated  with  the  condition. 

Another  pathological  change  which  may  accompany 
lesions  of  the  pancreas  is  the  condition  known  as  fat 
necrosis,  first  adequately  described  by  Balser.  Fat 
necrosis  is  an  index  of  pancreatic  disease,  and,  occurring 
when  the  pancreatic  juice  finds  its  way  into  neighboring 


8  PREFACE. 

tissue,  bears  much  the  same  relation  to  lesions  of  the 
pancreas  as  does  jaundice  to  hepatic  disease.  Recog- 
nition of  the  lesion  and  its  significance  is  of  import  to 
the  surgeon  as  well  as  of  purely  pathological  interest. 

The  etiology  of  pancreatic  diseases  presents  problems 
which  have  long  remained  unexplained.  Lesions  ot 
the  organ  seldom  occur  as  primary  or  isolated  condi- 
tions, but  are  usually  consequent  upon  changes  in  the 
adjacent  duodenum,  in  the  liver,  or  in  the  bile  passages. 
Abundant  proof  will  be  brought  that  either  acute  hem- 
orrhagic pancreatitis  or  chronic  interstitial  inflammation 
may  be  produced  by  biliary  calculi.  An  intimate  rela- 
tion exists  between  chronic  inflammatory  lesions  of  the 
liver  and  those  of  the  pancreas,  both  being  produced 
by  the  action  of  similar  etiological  factors  ;  acute  or 
chronic  lesions  may  result  from  infection  of  the  pancre- 
atic duct  having  its  origin  in  the  duodenum. 

In  the  following  chapters  an  attempt  has  been  made 
to  approach  the  unsolved  questions  which  concern  this 
orean.     Access  to  a  considerable  material  available  in 

o 

the  Pathological  Laboratory  of  the  Johns  Hopkins 
Hospital  has  given  abundant  opportunity  for  the  study 
of  various  lesions  of  the  gland  and  the  associated  con- 
ditions. To  the  encouraging  interest  of  Dr.  William  H. 
Welch  I  am  indebted  for  many  helpful  suggestions. 
Additional  material  has  been  obtained  through  the  kind- 
ness of  Dr.  Simon  Flexner,  of  the  University  of  Penn- 
sylvania.    Experiments  have  been  undertaken  and  the 


PREFACE.  9 

literature  of  each  subject  has  been  reviewed.  The 
Rockefeller  Institute  of  Medical  Research  has  aided 
the  completion  of  the  work. 

Conditions  peculiar  to  the  organ  have  received  most 
attention,  and  it  has  not  been  considered  desirable  to 
make  an  exhaustive  study  of  those  lesions  which  pre- 
sent no  characteristic  features  and  bear  no  special 
relation  to  the  peculiar  physiology  of  the  organ.  Hence 
the  incidence  of  tuberculosis  has  not  been  discussed, 
because  the  lesion  in  the  pancreas  presents  no  distinctive 
features.  For  the  same  reason  acute  suppurative  inflam- 
mation does  not  deserve  the  attention  devoted  to  acute 
hemorrhagic  pancreatitis,  since  the  latter,  long  unex- 
plained, is  a  condition  dependent  upon  characteristic 
anatomical  and  physiological  peculiarities  of  the  gland. 
The  etiology  of  chronic  inflammation  is  characteristic  ; 
the  consequent  lesions  bear  varying  relations  to  differ- 
ent histological  structures  of  the  organ,  and  at  times 
produce  such  functional  alterations  that  the  gland  is  no 
longer  capable  of  exerting  its  normal  influence  upon 
metabolism.  The  rare  condition  known  as  haemochro- 
matosis  has  been  studied  in  detail,  because  it  illustrates 
the  relation  of  diabetes  mellitus  to  a  form  of  pancrea- 
titis of  which  the  pathogenesis  is  explicable.  Since  the 
material  at  my  disposal,  as  might  be  expected,  does 
not  add  new  facts  to  the  much-studied  etiology  and 
pathology  of  new  growths  and  cysts,  these  subjects 
have  not  been  treated  in  detail. 


lO  PREFACE. 

Pathological  changes  in  the  gland  have  emphasized 
the  importance  of  certain  gross  anatomical  and  histo- 
logical features,  and  for  this  reason  the  first  chapters  of 
the  present  work  have  been  devoted  to  the  normal 
structure  of  the  organ.  The  attempt  has  been  made 
to  give  a  systematic  account  of  the  anatomy  of  the 
gland,  emphasizing  those  peculiarities  which  have  a 
bearing  upon  subsequent  studies,  and  treating  curso- 
rily the  details  of  structure  which  are  described  in 
all  text-books  of  anatomy.  The  dependence  of  acute 
and  chronic  inflammation  upon  changes  in  the  biliary 
passages  has  given  importance  to  structural  details 
which  had  been  previously  regarded  as  little  worthy  of 
consideration  ;  hence  the  form  and  size  of  the  ducts 
and  their  outlets  have  been  studied  with  a  minuteness 
which  may  seem  at  first  sight  unnecessary.  In  the 
chapter  upon  histology  special  attention  has  been 
directed  to  the  islands  of  Langerhans,  for  few  facts 
concerning  their  development,  structure,  and  function 
are  not  mooted.  The  physiology  of  the  pancreas  has 
not  been  treated  in  a  separate  chapter,  since  on  the 
one  hand  facts  relating  to  the  so-called  external  secre- 
tion are  well  understood,  while  on  the  other  hand 
the  data  upon  which  is  based  our  knowledge  of  its 
internal  function  belong  as  much  to  the  domain  of 
pathological  as  of  normal  physiology,  and  have  been 
reviewed  in  the   chapter  on    diabetes.      Here,   as  else- 


PREFACE. 


1 1 


where,  observation  of  diseased  condidons  has  indicated 
the  function  of  normal  structures. 

Throughout  the  following  pages  are  numerous  ref- 
erences to  the  symptomatology  of  pancreatic  disease. 
Since  lesions  of  the  pancreas  are  seldom  primary,  their 
clinical  manifestations  are,  as  Friedreich  pointed  out, 
obscured  by  accompanying  disease  of  adjacent  organs. 
The  recognition  of  pancreatic  lesions,  their  causes  and 
their  consequences,  is  of  great  importance,  not  only  to 
the  physician,  but  notably  to  the  surgeon  who  opens 
the  abdomen.  For  illustration,  disseminated  fat  necrosis 
indicates  grave  disease  of  the  gland  ;  acute  pancrea- 
titis is  a  not  infrequent  consequence  of  cholelithiasis  ; 
while  chronic  pancreatitis,  which  accompanies  the  same 
condition,  is  frequently  mistaken  for  malignant  growth. 
To  the  student  of  internal  medicine  few  conditions  pre- 
sent greater  difficulties  of  diagnosis  than  do  the  various 
forms  of  pancreatic  disease ;  but  with  increasing  knowl- 
edge of  their  etiology,  their  nature,  and  their  relation 
to  other  diseases,  means  for  their  recognition  are  closer 
to  hand. 


CONTENTS. 


CHAPTER  PAGE 

I.     The    Anatomy  of   the    Pancreas    and    its    Varia- 
tions  .  .  .  .  .  .  .          .  .17 

11.     Anomalies  of  the  Pancreas    .  .  .  .  .46 

III.  Histology  of  the  Pancreas — The  Islands  of  Lan- 

GERHANS  .  .  .  .  .  .  .  -67 

IV.  Varieties  of  Acute  Pancreatitis    .  .          .          .89 
V.     The     Etiological    Relation    of    Gall-Stones    to 

Acute  Hemorrhagic  Pancreatitis.    Hemorrhagic 
AND  Gangrenous  Pancreatitis    .         .         .         -113 
VI.     Fat  Necrosis  .         .         .         .         .         .         .         -135 

VII.     The  Varieties   of    Chronic   Interstitial   Pancrea- 
titis    .  .  .          .         .         .         .         .  163 

VIII.     The    Etiology   of    Chronic    Interstitial    Pancrea- 
titis    .  .         .  .  .  .  .          .  .    184 

IX.     Hyaline  Degeneration  of  the  Pancreas        .          .214 
X.     The  Pathology  of  Diabetes  Mellitus    .  .          -236 

XI.     The  Relation  of  Diabetes  Mellitus  to  Lesions  of 

the  Pancreas       .  .  .  .          .  .  .261 

XII.     Hemochromatosis  and  Bronzed  Diabetes       .          .281 
XIII.     The  Symptoms  and  Treatment  of  Pancreatic  Dis- 
ease  .........     304 

Bibliography  .......     339 

Index 355 


List   of  Illustrations. 

FIGURE  PAGE 

I.   Original  drawing  of  Wirsung,  showing  the  pancreatic  duct  .      i8 
.2.   Reproduction  of  the  original  drawing  of  Santorini,  show- 
ing both  ducts  of  the  pancreas       .  .  .  .  •      1 9 

3.  Development  of  the  pancreas    in  the   sheep,   after  Stoss, 

slightly  modified  .  .  .  .  .  .  -23 

4.  Reproduction  of  a  drawing  of  Santorini,  published  in  1775, 

by  Girardi  ........      26 

5.  Varying  relations  of  the  duct  of  Santorini  to  the  duct  of 

Wirsung     .  .  .  .  .  .  .  '       .  -31 

6.  Varying  relations  of  the  duct  of  Santorini  to  the  duct  of 

Wirsung     .  .  .  .  .  .  .  .  -32 

7.  Diagrammatic  drawing  of  the  pancreas,  showing  the  two 

lobes  which  form  the  head   .  .  .  .  .  -36 

8.  Diagram  showing  diverticulum  of  Vater  containing  a  cal- 

culus .........      40 

9.  Supporting    connective-tissue    framework   of  a   pancreatic 

lobule  after  digestion  of  the  parenchyma  by  pancreatin      70 

10.  Chronic  interstitial  pancreatitis  in  the  cat,  following  liga- 

tion of  the  pancreatic  ducts .  .  .         .          .  -71 

1 1 .  Camera  lucida  tracing  of  the  lobule  boundaries  in  one  of 

a   series  of  sections    from    the   splenic    end  of  a   cat's 
pancreas     .  .  .  .  .  .  .  .  -72 

IS 


1 6  LIST    OF    ILLUSTRATIONS. 

FIGURE 

12.  Gall-stones  from  Case  I.  C actual  size) 

13.  Experimental  fat  necrosis  ..... 

14.  Congenital  syphilitic  pancreatitis       .... 

15.  Chronic  interstitial  pancreatitis  following  duct-obstruction 

16.  Chronic  interstitial  pancreatitis  of  interacinar  type 

17.  Biliar}-  calculus  (actual  size)  .... 

18.  Hyaline  degeneration  of  the  pancreas 

19.  Drawing  made  with  low  magnification  (colored  plate; 

20.  Drawing    made    with    a    higher    magnification     (colored 

plate)         .  .  .  .  .  .  .  .  .220 

21.  Calculi  which  in  Case  XXXIII.  were  at  operation  removed 

from  the  gall-bladder  .......   330 


PAGK 

.   102 

•   150 

.   166 

.   176 

.   182 

.   189 

.   216 

220 

DISEASE 

OF 

THE    PANCREAS. 


CHAPTER    I. 

THE    ANATOMY    OF    THE    PANCREAS    AND    ITS    VARIATIONS. 

The  pancreas  is  subject  to  greater  variation  in  size 
and  shape  than  other  important  glandular  organs. 
The  ducts  of  the  glands  vary  widely  in  their  confor- 
mation and  in  their  relation  to  one  another  and  to 
the  common  bile  duct.  In  a  limited  number  of  in- 
stances an  accessory  duct  is  capable  of  assuming  the 
function  of  the  larger  outlet ;  the  larger  duct  usually 
unites  with  the  common  bile  duct  before  it  enters  the 
intestine,  but  in  a  considerable  number  of  cases  the 
two  ducts  are  wholly  separated.  Only  by  a  study  of 
many  specimens  is  it  possible  to  determine  the  rela- 
tive frequency  of  anatomical  peculiarities  which  have  a 
physiological  significance  and  constitute  an  important 
factor  in  the  production  of  certain  pathological  altera- 
tions. 

2  17 


1 8  DISEASE   OF   THE    PANCREAS. 

The  descriptions  of  the  pancreas  given  by  text-books 
of  anatomy  var}^  little,  but  I  believe  may  be  so  modified 
as  to  give  a  clearer  conception  of  the  topography  of 
the  gland.  A  few  well-known  facts  may  be  recalled  in 
order  to  make  clear  the  subsequent  description. 

The  right  extremity  of  the  pancreas  lying  in  the  con- 
cavity of  the  duodenum  being  wider  and  thicker  than 
the  remainder  of  the  gland,  is  termed  the  head,  and 
forms  an  enlarged,  somewhat  bulbous  mass,  of  which 
the  long  axis  makes  an  angle  with  the  remainder  of  the 
gland,  A  constricted  part,  or  neck,  connected  with  the 
upper  and  anterior  aspect  of  the  head,  at  first  directed 
slightly  upward  and  forward,  is  continued  to  the  right 
as  the  body  of  the  gland.  In  contact  with  this  neck,  in 
the  groove  which  causes  its  constriction,  lie  the  superior 
mesenteric  vessels  which  pass  from  behind  below  the 
organ,  while  a  short  process  of  the  head  projects  behind 
these  vessels,  thus  deepening  the  groove  in  which  they 
lie.  The  body  terminates  near  the  spleen  in  a  slightly 
tapering  extremity  called  the  tail,  but  no  line  of  demar- 
cation exists  between  these  two  parts.  The  larger 
duct  of  the  gland,  the  duct  of  Wirsung,  traverses  the 
organ  from  left  to  right,  bends  downward  and  back- 
ward in  the  neck,  and,  approaching  the  posterior  sur- 
face of  the  head,  finally  reaches  the  wall  of  the  duo- 
denum, which  it  penetrates  after  uniting  with  the 
common  bile  duct. 

According  to  Shirmer,  who  has  collected  many  his- 


Fig.  2. — Reproduction  of  the  original  drawing  of  Santorini,  showing  both  ducts  of  the  pancreas. 


THE  ANATOMY  OF  THE  PANCREAS.      19 

torical  data  concerning  the  pancreas,  the  older  writers, 
inckiding  Galen,  Vesalius,  and  Fallopius,  believed  that 
the  organ  existed  to  support  and  protect  more  impor- 
tant structures  in  contact  with  it.  The  recognition  of 
its  physiological  significance  was  possible  only  after  the 
discovery  of  Wirsung,  in  1643,  ^^at  it  is  traversed  by 
a  duct  which,  receiving  branches  from  every  side,  in- 
creases in  size,  and  finally  opens  into  the  duodenum 
(see  Fig.  i).  Shirmer  states  that  Moritz  Hoffmann 
had  previously  seen  a  duct  within  the  pancreas  of  the 
turkey.  Wirsung,  studying  the  duct  in  man  and  in 
lower  animals,  observed  that  it  was  sometimes  double  ; 
and  Albrecht  von  Haller  found  that  it  was  often  pro- 
vided with  a  branch  which,  diminishing  in  size,  pene- 
trated the  intestine  at  a  point  removed  from  the  ori- 
fice of  the  main  duct. 

Santorini,  however,  first  recognized  that  two  ducts 
are  normally  present ;  he  described  and  accurately 
pictured^  the  smaller  duct,  to  which  his  name  has  been 
given.  According  to  his  description,  it  terminates  in 
a   small  papilla   situated  upon  the  mucous  membrane 

^  Figs.  2  and  4  are  reproduced  from  the  excellent  plates  of  Santo- 
rini, published  in  1775,  thirty-eight  years  after  his  death,  by  Michael 
Girardi,  under  the  title,  "Jo.  Dominici  Santorini  anatomici  summi 
septemdecim  tabulae  quas  nunc  primum  edit  atque  explicat  iisque 
alias  addit  de  structura  mammarum  et  de  tunica  testis  vaginali. ' '  For 
the  opportunity  to  reproduce  these  plates  I  am  indebted  to  the  kind- 
ness of  Dr.  Howard  A.  Kelly,  from  whose  library  this  volume  was 
obtained. 


20  DISEASE    OF   THE   PANCREAS. 

of  the  duodenum,  about  two  fingers'  breadths  nearer 
the  stomach  than  the  larger  papilla  in  which  terminates 
the  larger  pancreatic  duct  and  the  common  bile  duct. 

Subsequent  anatomists,  including  Meckel  and  Cru- 
veilhier,  failed  to  recognize  the  existence  of  two  ducts 
and  thought  that  the  occurrence  of  an  accessory  duct 
was  exceptional  until  Claude  Bernard,  in  his  memoir 
upon  the  pancreas,  described  the  second  smaller  outlet 
as  constantly  present.  According  to  Claude  Bernard,  it 
appears  to  be  formed  by  bifurcation  of  the  larger  duct, 
but,  unlike  the  latter,  diminishes  in  calibre  as  it  ap- 
proaches the  intestine  ;  he  found  that  the  duct  which 
opens  nearer  the  stomach  is  occasionally  larger  than 
that  which  terminates  with  the  common  bile  duct  in  the 
ampulla  of  Vater,  while  in  certain  instances,  on  the 
contrary,  the  smaller  duct  is  partially  obliterated  in  the 
neighborhood  of  its  intestinal  extremity. 

The  number  of  ducts  varies  in  different  animals,  and 
more  than  one  are  usually  present.  In  birds  from  one 
to  three  ducts  are  present,  the  latter  number  being 
found  by  De  Graaf  in  hens,  pigeons,  and  magpies  as 
early  as  1751.  Among  most  mammals  the  adult,  as  is 
well  known,  possesses  two  ducts,  one  of  which  joins  the 
common  bile  duct.  The  pancreas  of  the  cat  and  of 
the  dog  consist  of  two  parts,  an  upper  horizontal  arm 
extending  from  the  duodenum  to  the  spleen  and  a 
descending  arm  lying  in  contact  with  the  duodenum 
and  projecting  into  the  duodenal   mesentery.     In   the 


THE  ANATOMY  OF  THE  PANCREAS.      2 1 

cat  a  large  duct,  sending  out  branches  into  both  arms 
of  the  gland,  enters  the  intestine  by  a  common  orifice 
with  the  bile  duct,  while  a  short  distance  below  a  much 
smaller  duct,  anastomosing  with  the  larger  in  the  sub- 
stance of  the  gland,  enters  the  duodenum.  In  the  dog 
the  larger  pancreatic  duct  enters  the  intestine  several 
centimetres  below  the  smaller,  which  joins  the  common 
bile  duct.  In  the  rabbit,  of  which  the  pancreas  consists 
of  lobules  scattered  in  the  mesentery,  a  large  duct  enters 
the  intestine  below  the  bile  duct,  while  the  smaller  duct 
is  so  atrophied  that  it  is  almost  impermeable. 

Development  of  the  Pancreas. — With  an  increased 
knowledge  of  the  development  of  the  gland  pecu- 
liarities of  the  ducts  have  been  better  understood. 
Earlier  investigations  seemed  to  show  that  the  devel- 
opment of  the  organ  varied  greatly  among  different 
classes  of  vertebrates,  but  more  careful  observations 
have  shown  considerable  uniformity.  In  all  vertebrates 
the  organ  begins  its  development  as  an  outgrowth  or 
diverticulum  from  the  wall  of  the  intestinal  tube,  and 
by  multiplication  of  cells  and  repeated  branching  this 
tubular  structure  gives  rise  to  the  complicated  tissue  of 
the  adult  organ. 

The  development  of  the  liver  begins  before  that  of 
the  pancreas,  at  a  period  when  the  gastrointestinal 
tract  is  an  almost  straight  tube  ;  the  liver  makes  its 
appearance  as  a  projection  upon  the  ventral  wall  of 
what   will    subsequently  become   the    duodenum.     At 


2  2  DISEASE    OF   THE    PANCREAS. 

a  slightly  later  period  proliferation  of  cells  in  the  dor- 
sal wall  of  the  intestine  forms  a  projecting  outgrowth 
which  represents  the  earliest  rudiment  of  the  pancreas. 
Upon  the  ventral  aspect  of  the  intestine  on  either  side 
of  the  hepatic  diverticulum  appear,  according  to  most 
recent  observers,  two  additional  epithelial  buds,  which 
increase  in  size  and  by  fusion  or  by  partial  atrophy  give 
rise  to  a  single  mass.  By  subsequent  growth  this  ven- 
tral mass  unites  with  the  larger  mass  which  has  arisen 
from  the  dorsal  outgrowth. 

Numerous  investigations  have  demonstrated  that  a 
dorsal  outgrowth  and  two  ventral  buds  in  close  prox- 
imity to  the  hepatic  outlet  represent  the  primitive  rudi- 
ment or  "  anlage"  of  the  pancreas  in  a  variety  of  diverse 
vertebrate  species.  The  occurrence  of  a  single  dorsal 
and  two  ventral  outgrowths  has  been  described  in  vari- 
ous species  of  fish  by  Laguesse,  von  Kupffer,  Hammar, 
Stohr,  and  Goppert  (quoted  by  Oppel).  In  the  sturgeon, 
however,  von  Kupffer  claims  to  have  found  four  rudi- 
mentary buds,  the  dorsal  outgrowth,  like  the  ventral, 
being  at  first  double.  In  amphibia  three  original  out- 
growths have  been  found  by  Gotte,  Goppert,  and  Felix  ; 
while  in  reptiles  similar  observations  have  been  made 
by  Brachet  and  others,  though  Volker  has  recently 
claimed  that  in  the  lizard — Lacerta  agilis — the  organ 
develops  from  a  single  dorsal  outgrowth. 

In  mammals  three  rudimentary  buds,  one  dorsal  and 
two  ventral,    have  been    described    by    Stoss  for   the 


THE  ANATOMY  OF  THE  PANCREAS. 


23 


sheep  and  by  Felix  for  the  cat,  while  analogous  obser- 
vations have  been  made  upon  human  embryos.  Volker, 
however,  differing  from  other  recent  embryologists,  has 
found  only  two  rudimentary  outgrowths,  one  dorsal  and 
one  ventral. 


Fig.  3. — Development  of  the  pancreas  in  the  sheep,  after  Stoss,  slightly  modified.  D,  duode- 
num; Pd,  dorsal  "anlage"  of  the  pancreas;  Pv,  ventral  "anlage"  of  the  pancreas;  Dc,  ductus 
choledochus  ;   G  B,  gall-bladder  ;    V,  umbilical  vein  ;    iy>,  portal  vein. 

Stoss  has  carefully  described  the  development  of  the 
pancreas  in  the  sheep.  The  bud-like  outgrowth  from 
which  the  liver  develops  is  formed  at  a  time  when  the 
gastro-intestinal  tract  is  a  straight  tube  attached  by  its 
mesentery  to  the  posterior  abdominal  wall.  The  pan- 
creas makes  its  appearance  as  a  projection  (Fig.  3,  i., 
Pd)  upon  the  dorsal  surface  of  the  intestine  between 
the  liver  and  the  stomach,  which  is  now  represented  by 


24 


DISEASE    OF   THE    PANCREAS. 


a  spindle-shaped  dilatation  of  the  intestinal  tube.  Upon 
the  ventral  surface  of  the  intestine,  at  either  side  of  the 
hepatic  duct,  appear  two  diverticula  (Fig.  3,  ii.,  Pv) 
which  later  fuse  to  form  the  ventral  rudiment  of  the  pan- 
creas and  subsequently  grow  to  meet  the  dorsal  part. 

The  stomach  at  first  lies  in  the  median  plane  of  the 
body,  and  that  part  which  is  to  become  the  greater 
curvature  is  now  the  posterior  or  dorsal  border  of  the 
organ.  The  alteration  of  position  by  which  the  stomach 
becomes  transversely  placed,  the  posterior  wall  becom- 
ing the  inferior  border  or  greater  curvature,  is  accom- 
panied by  a  corresponding  change  in  the  position  of 
the  duodenum  and  pancreas.  The  dorsal  part  of  the 
pancreas,  which  has  pushed  its  way  into  the  dorsal 
mesentery  of  the  intestinal  tube,  comes  to  lie  trans- 
versely with  its  left  extremity  near  the  spleen,  and  at 
the  same  time,  as  Stoss  has  shown,  that  part  of  the 
duodenum  to  which  the  pancreas  and  liver  are  attached 
twists  upon  its  longitudinal  axis  in  such  a  way  that  the 
ventral  wall,  and  with  it  the  openings  of  the  bile  duct 
and  ventral  pancreatic  outgrowth,  passes  to  the  right 
and  backward  (Fig.  3,  v.),  becoming  the  posterior  wall 
of  the  duodenum.  With  further  growth  the  part  of  the 
pancreas  which  was  originally  ventral  comes  into  con- 
tact with  the  larger  dorsal  part  of  the  organ.  The  two 
parts  unite  to  form  a  conglomerate  organ  and  the  two 
ducts,  which  were  at  first  separate,  anastomose.  At  an 
early  stage  the  duct  of  the  dorsal  part  atrophies,  and 


THE  ANATOMY  OF  THE  PANCREAS.      25 

finally  disappears,  so  that  the  single  opening  which 
remains  in  the  adult  sheep  is  that  of  the  ventral  out- 
growth. 

Stoss  in  the  sheep  and  Wlassow  in  the  pig  found  the 
dorsal  outgrowth  bilobed  at  an  early  period  of  develop- 
ment, and  think  that  like  the  ventral  part  of  the  organ 
it  may  be  originally  double.  Choronschizky,  who  has 
in  great  part  confirmed  the  observations  of  Stoss,  has 
found  the  dorsal  outgrowth  always  single,  and  believes 
that  the  bilobed  appearance  observed  by  Stoss  and 
Wlassow  is  the  result  of  its  early  branching.  Helly  has 
reached  the  same  conclusion. 

The  development  of  the  human  pancreas,  according 
to  most  recent  observations,  does  not  differ  from  that 
of  other  vertebrates.  Earlier  observers,  Phisalix,  Zim- 
mermann,  and  Hamburger,  and  recently,  as  before 
mentioned,  Volker,  have  described  two  primitive  out- 
growths. Felix  has,  however,  found  three  "anlage,"  a 
dorsal  and  a  right  and  rudimentary  left  ventral,  the  two 
latter  subsequently  fusing.  The  dorsal  rudiment,  aris- 
ing between  the  bile  duct  and  stomach,  forms  the  ductus 
Santorini,  the  ventral  the  ductus  pancreaticus  (Wir- 
sungianus).  Jankilowitz  has  found  in  a  human  embryo 
forty-seven  millimetres  in  length  a  dorsal  outgrowth 
projecting  into  the  mesentery,  and  on  either  side  of  the 
ductus  choledochus  an  additional  projection.  The  oc- 
currence of  such  a  triple  origin  has  been  further  con- 
firmed by  von   Brunn.     In  an    embryo  six  weeks   old 


26  DISEASE    OF    THE    PANCREAS. 

Hamburger  has  found  the  dorsal  and  ventral  parts  of 
the  o-land  united,  and  concludes  that  anastomosis  occurs 
during  the  second  half  of  the  second  month  of  embry- 
onic life. 

Variation  of  the  Pancreatic  Ducts. — Embryological 
study  has  shown  that  the  greater  part  of  the  pancreas, 
the  body  and  part  of  the  head,  develops  from  the 
primitive  dorsal  outgrowth  represented  in  the  adult 
by  the  duct  of  Santorini,  which  enters  the  duodenum 
between  the  bile  papilla  and  the  stomach  (Fig.  4).  The 
duct  of  Wirsung  enters  the  duodenum  in  common  with 
the  ductus  choledochus  below  the  duct  of  Santorini, — 
that  is,  at  a  point  farther  from  the  stomach, — and  in  the 
head  of  the  gland  represents  the  primitive  ventral  out- 
growth. The  two  ducts  usually  anastomose  at  an  early 
period.  That  part  of  the  upper  or  originally  dorsal 
duct  which  lies  between  the  duodenal  orifice  and  its 
anastomosis  with  the  lower  duct  undergoes  partial 
atrophy,  and  the  lower  channel  increasing  in  size  ap- 
pears to  be  a  continuation  of  the  large  duct  which, 
derived  from  the  dorsal  outgrowth,  follows  the  axis  of  the 
gland.  Hence  the  duct  of  Wirsung,  which  affords  an 
outlet  for  almost  the  entire  pancreatic  secretion,  is  de- 
rived in  the  head  of  the  gland  from  the  ventral  pan- 
creas and  in  the  body  from  the  dorsal. 

In  a  certain  number  of  cases  the  upper  duct,  or  duct 
of  Santorini,  remains  larger  than  the  lower  ;  in  other  in- 
stances there  is  no  anastomosis  between  the  two  ducts. 


;Ese=-=^^ -. 


'"^ 


Fig.  4. — Reproduction  of  a  drawing  of  Santorini.  published  in  1775,  by  Girardi.  The  duode- 
num has  been  opened,  and  both  the  bile  papilla  and  the  papilla  of  the  smaller  pancreatic  duct  are 
exposed. 


THE  ANATOMY  OF  THE  PANCREAS.      27 

Claude  Bernard,  Henle,  Sappey,  and  other  anatomists 
have  described  various  modifications  to  which  the  ducts 
are  subject,  while  more  recently  statistical  data  have 
been  furnished  by  study  of  a  considerable  number  of 
specimens.  Increased  importance  has  been  given  to 
the  relationship  of  the  pancreatic  ducts  to  one  another 
and  to  the  common  bile  ducts  by  the  study  of  patho- 
logical lesions  dependent  upon  these  anatomical  pe- 
culiarities. 

Shirmer  has  examined  the  pancreatic  ducts  in  one 
hundred  and  four  bodies.  In  order  to  test  their  patency 
he  exposed  the  larger  duct  in  the  body  of  the  gland  and, 
inserting  a  cannula,  forced  air  in  the  direction  of  the 
duodenum,  which  had  been  previously  opened.  By 
keeping  the  specimens  under  water,  the  escape  of  air 
from  one  or  both  ducts  was  determined.  The  ducts 
were  later  carefully  dissected.  Shirmer  described  nu- 
merous varieties  dependent  upon  the  relative  size  of 
the  two  ducts,  their  anastomosis  within  the  gland,  their 
patency,  and  their  relation  to  the  bile  duct.  He  at- 
tempted no  classification  of  the  diverse  forms,  but  for 
the  sake  of  clearness  they  may  be  collected  into  three 
groups,  as  follows  : 

(i)  In  sixty-six  of  the  one  hundred  and  four  speci- 
mens two  patent  ducts  anastomosed  within  the  gland. 
Of  these  fifty-seven  represented  what  Shirmer  regarded 
as  the  usual  or  normal  condition  ;  upon  the  mucosa  of 
the  duodenum  were  two  papilla,  a  smaller   nearer  the 


28  DISEASE    OF   THE   PANCREAS. 

stomach  and  a  larger  situated  below  the  smaller  and 
containinor  the  common  termination  of  the  bile  duct 
and  the  duct  of  Wirsung  ;  the  duct  of  Santorini,  which 
terminated  in  the  smaller  papilla,  joined  the  duct  of 
Wirsung  several  centimetres  from  the  duodenum. 
In  three  cases  the  upper  duct,  or  duct  of  Santorini, 
was  larger  than  the  duct  of  Wirsung,  though  otherwise 
their  relations  were  those  usually  present.  In  six  cases, 
Shirmer  states,  the  bile  duct  entered  the  intestine  with 
the  upper  duct,  which  in  three  of  these  cases  was  larger 
than  the  lower. 

(2)  In  twenty-nine  instances  one  or  other  of  the  two 
ducts  was  wholly  or  partially  obliterated.  In  twenty-two 
of  these  specimens  the  upper  papilla  was  not  patent ; 
and  in  two  instances  there  was  no  upper  papilla.  In 
four  examples  the  upper  duct  alone  existed  while  the 
ductus  choledochus  entered  the  intestine  unaccompan- 
ied by  a  pancreatic  duct.  In  one  instance  the  duct  of 
Santorini  and  the  bile  duct  entered  the  intestine  to- 
gether ;  a  second  papilla  was  found  in  the  duodenum 
farther  from  the  stomach,  but  was  not  patent. 

(3)  In  nine  specimens  both  ducts  were  present, 
though  they  failed  to  anastomose  within  the  gland.  In 
four  of  these  cases  the  upper  duct  was  larger  than  the 
lower  and  joined  the  common  bile  duct.  In  the  five 
remaining  specimens  the  larger  duct  terminated  in  the 
lower  papilla  with  the  bile  duct. 

I  have  dissected  the  pancreatic  ducts  in  one  hundred 


THE  ANATOMY  OF  THE  PANCREAS. 


29 


specimens.  In  order  to  determine  their  patency  and, 
if  possible,  the  existence  of  an  anastomosis  between 
them  a  solution  of  Berlin  blue  was  injected  into  the 
duct  of  Wirsung  exposed  by  transverse  section  of  the 
body  of  the  gland.  To  avoid  extravasation  the  injection 
was  made  at  a  low  pressure,  little  more  than  that  of  a 
column  of  water  two  feet  in  height.  By  compressing 
that  orifice,  from  which  the  fluid  readily  escaped,  the 
attempt  was  made  to  divert  the  flow  to  a  second  orifice. 
Such  specimens  were  hardened  in  formalin  and  subse- 
quently preserved  in  alcohol ;  the  dissection  of  the 
ducts  was  facilitated  by  the  presence  of  the  injected 
material.  In  those  instances  in  which  the  lesser  papilla 
appeared  to  be  closed,  serial  sections  were  made  in 
order  to  more  accurately  determine  its  patency. 

My  observations  differ  in  several  respects  from  those 
of  Shirmer.  Though  the  ducts  vary  much  in  their 
relative  size  and  one  has  at  times  undergone  partial 
obliteration,  two  are  constantly  present.  In  twelve 
instances  Shirmer  found  that  the  common  bile  duct 
joined  the  upper  pancreatic  duct  while  farther  from 
the  stomach  was  a  second  smaller  papilla.  His 
observation  is  difficult  to  explain,  for  in  my  specimens 
the  relationship  of  the  duct  of  Wirsung  to  the 
common  bile  duct  is  constant,  as  might  be  expected 
from  the  well-established  embryological  facts  already 
cited. 

In  ninety  specimens  the  two  ducts  are  united,  but  in 


T^O  DISEASE    OF   THE   PANCREAS. 

ten  two  wholly  independent  ducts  enter  the  Intestine. 
In  eighty-nine  cases  the  duct  of  Wirsung  is  larger  than 
the  duct  of  Santorini.  In  twenty-one  instances  the  duct 
of  Santorini  is  apparently  obliterated  near  its  termi- 
nation. The  varieties  found  are  indicated  in  the  follow- 
ing classification  : 

I.  Ducts  in  anastomosis. 

(i)   Duct  of  Wirsung  larger, 

(a)  Duct  of  Santorini  patent      ...62, 
{b)  Duct  of  Santorini  not  patent     .     .21 

(2)   Duct  of    Santorini  larger    or   equal    in 
size  to  the  duct  of  Wirsung. 
{a)   Duct  of  Wirsung  patent ....     6 

(b)  Duct  of  Wirsung  not  patent     .     .     o 

II.  Ducts  not  in  anastomosis, 

(i)  Duct  of  Wirsung  larger 5 

(2)  Duct  of  Santorini  larger 5 

In  considerably  more  than  one-half  the  specimens 
both  ducts  are  patent,  and  the  duct  of  Wirsung,  which 
unites  with  the  duct  of  Santorini,  is  larger  than  the  lat- 
ter (Fig.  5,  i.) ;  the  duct  of  Santorini  diminishes  in  size 
as  it  approaches  the  duodenum,  and  opens  upon  the 
lesser  papilla  by  a  narrow  orifice.  Receiving  numerous 
branches  from  the  head  of  the  gland,  and  gradually  in- 
creasing in  size  as  the  duct  of  Wirsung  is  approached, 
the  duct  of  Santorini  appears  to  be  a  branch  of  the 
larger  duct  into  which,  in  the  majority  of  instances,  it 
doubtless  pours  its  secretion.     In   only  forty-eight  in- 


THE  ANATOMY  OF  THE  PANCREAS. 


31 


Stances  was  it  possible  to  inject  fluid  at  a  low  pressure 
through  the  smaller  papilla.  In  some  of  these  cases,  how- 
ever, the  injected  fluid  escaped  readily,  and  hence  it  is 


Fig.  5. — Varying  relations  of  the  duct  of  Santorini  (s)  to  the  duct  of  Wirsung  (w).     Drawn  from 

dissected  specimens. 

probable  that  the  duct  may  occasionally  act  as  a  func- 
tional outlet.  In  fifteen  specimens  the  patency  of  the 
duct  was  demonstrated  only  by  microscopic  examina- 


32 


DISEASE    OF   THE   PANCREAS. 


tion  of  serial  sections  through  the  lesser  papilla,  while 
in  a  very  large  group  of  cases  it  was  not  possible  even 
by  that  means  to  demonstrate  its  patency.  Hence  in 
more  than  half  of  all  individuals  the  lesser  duct  is  at 
its  orifice  obliterated  or  so  constricted  that  it  cannot 
assume  the  function  of  the  larger  when  occluded. 

Occasionally  the  duct  of  Santorini  enters  the  upper 
aspect  of  the  duct  of  Wirsung  (Fig.  5,  i.)  ;  at  times 
it  arises    from    the    lower    aspect   (Fig.   6,    i.,   ii.),   and 


Fig.  6.— Var>'ing  relations  of  the  duct  of  Santorini  (s)  to  the  duct  of  Wirsung  (to).     Broken  lines 
are  in  the  plane  of  the  interlobular  fissure.     Drawn  from  dissected  specimens, 

by  a  somewhat  tortuous  course  reaches  the  upper 
papilla.  The  point  at  which  the  anastomosis  occurs 
varies  considerably,  and  though  usually  several  centi- 
metres from  the  termination  of  both  ducts,  may  be  less 


THE  ANATOMY  OF  THE  PANCREAS.      ^^ 

than  a  centimetre  from  the  duodenal  orifice  of  one,  the 
other  duct  then  following  a  tortuous  course  to  reach 
its  termination  (Fig.  6,  iii.,  iv.).  Occasionally  the  duct 
of  Santorini  appears  to  be  a  direct  continuation  of  the 
main  channel  within  the  body  of  the  gland  (Fig.  6,  iv.), 
thus  suggesting  the  original  embryonic  condition. 

In  ten  cases  (as  in  Fig.  5,  v.,  vi.,  vii.)  no  anastomosis  is 
found  between  the  two  ducts.  In  four  additional  cases, 
included  in  group  I.  of  the  table  (see  Fig.  5,  iii.),  the  duct 
of  Santorini  is  almost  wholly  independent  of  the  duct  of 
Wirsung,  with  which  it  is  united  only  by  a  narrow  twig. 
Receiving  branches  from  all  sides  and  gradually  in- 
creasing in  size  as  it  approaches  the  duodenum,  the 
duct  of  Santorini  in  such  a  case  represents  the  outlet 
for  a  part  of  gland  substance  and  is  functionally  inde- 
pendent of  the  lower  duct,  even  though  this  small 
communicating  twig  unites  them.  Indeed,  it  is  conceiv- 
able that  when  the  two  ducts  appear  to  be  wholly 
independent  a  very  minute  communication,  though 
present,  has  not  been  demonstrated. 

The  relative  diameter  of  the  two  ducts  varies  much. 
When  they  anastomose,  in  only  seven  of  ninety  cases 
is  the  duct  of  Santorini  equal  or  larger  (Fig.  5,  iv,),  but 
of  ten  cases  in  which  there  is  no  anastomosis,  in  half 
the  specimens  the  duct  of  Santorini  equals  or  exceeds 
the  duct  of  Wirsung  (Fig.  5,  vii.). 

Relation  of  Parenchyina  to  the  Ducts. — The  pancreas 
consists,  it  is  well  known,  of  lobules  held  together  by 


34 


DISEASE    OF   THE   PANCREAS. 


connective  tissue,  and  upon  the  surface  of  the  gland 
polygonal  areas,  varying  greatly  in  size  and  shape,  are 
mapped  out  by  clefts  filled  with  very  loose  areolar 
tissue.  By  carefully  dissecting  the  loose  tissue  which 
these  clefts  contain  the  gland  may  be  divided  into 
well-defined  masses  of  parenchyma.  Such  lobules, 
the  shape  of  which  is  dependent  upon  mutual  press- 
ure, are  usually  a  centimetre  or  more  across,  and  in 
the  body  and  tail  are  frequently  oblong,  with  a  long 
diameter  at  right  angles  to  the  axis  of  the  gland  ;  in 
the  head  they  are  irregular  in  shape.  These  relatively 
large  glandular  masses,  separated  by  loose  connective 
tissue,  are  found  to  be  further  divided  by  more  incon- 
spicuous and  less  well-defined  septa  into  smaller  lobules 
of  varying  size  and  shape,  usually  several  millimetres 
across.  Microscopic  examination  demonstrates  that 
these  are  again  divisible  into  even  smaller  ill-defined 
areas,  which  may  be  regarded  as  the  ultimate  units  of  the 
gland  structure.  These  smallest  units  may  be  desig- 
nated primary  lobules ;  the  larger  masses  secondary  lob- 
ules ;  while  the  largest  bodies,  separated  by  loose  areo- 
lar tissue,  may  be  conveniently  termed  tertiary  lobules. 
The  large  pancreatic  duct,  as  it  passes  through  the 
body  of  the  gland,  is  closely  beset  with  lateral  branches, 
which  are  most  numerous  upon  its  superior  and  inferior 
aspects  and  usually  make  an  oblique  angle  with  the 
main  channel.  These  branches  frequently  divide,  and 
from  a  branch  and  its  subdivisions  are  given  off  lateral 


THE  ANATOMY  OF  THE  PANCREAS.      35 

twigs  which  penetrate  the  tertiary  lobules.  In  some 
instances  the  duct  of  the  tertiary  lobule  may  enter 
directly  the  duct  of  Wirsung.  In  attempting  to  separate 
the  lobules  by  breaking  through  the  loose  tissue  which 
unites  them  it  is  usually  found  that  the  interlobular 
clefts  or  septa  do  not  reach  the  ducts  upon  which  the 
tertiary  lobules  are  situated,  but  the  boundaries  of  the 
latter  are  partially  obscured  by  secondary  lobules  in 
intimate  contact  with  the  wall  of  the  duct  and 
directly  tributary  to  it. 

In  the  head  of  the  gland  tertiary  lobules  preserve  a 
similar  relationship  to  the  two  ducts  there  present  and 
are  tributary  to  branches  or  sub-branches  of  the  duct 
of  Wirsung  or  of  the  duct  of  Santorini.  A  large 
branch  (Fig.  5,  i.  and  ii.,  x)  of  the  duct  of  Santorini 
usually  passes  downward  and  drains  a  large  part  of 
the  head,  while  a  similar  branch  (Fig,  5,  i.  and  ii.,  y) 
from  the  duct  of  Wirsung  near  its  junction  with  the 
duct  of  Santorini,  passing  downward  and  to  the  left, 
usually  enters  the  projection  (Fig.  7,  j/)  which  lies  behind 
the  superior  mesenteric  vessels.  From  that  part  of 
the  duct  of  Wirsung  which  lies  in  the  head  of  the  pan- 
creas branches  are  usually  small  and  enter  without 
subdivision  the  tertiary  lobules. 

From  the  arrangement  just  described  it  results  that 
the  head  of  the  gland  consists  of  two  distinct  sets  of 
lobules  grouped  about  the  two  ducts,  and  by  careful 
dissection,   more    readily   in    hardened   specimens,   this 


36  DISEASE    OF   THE    PANCREAS. 

condition  may  be  demonstrated.  These  two  groups  of 
lobules  are  separated  near  the  duodenum  by  loose 
areolar  tissue,  while  at  the  point  where  the  two  ducts 
anastomose  they  are  united.  The  head  of  the  pancreas 
(Fig.  7)  is  in  fact  composed  of  two  distinct  lobes,  which 


Fig.  7. — Diagrammatic  drawing  of  the  pancreas,  showing  the  two  lobes  which  form  the  head. 
The  interlobular  fissure  has  been  opened  by  dissection,  and  the  lower  part  (jr)  of  the  lobe  corre- 
sponding- to  the  duct  of  Santorini  has  been  drawn  upward  in  order  to  expose  the  lobe  correspond- 
ing to  the  duct  of  Wirsung. 

for  the  sake  of  convenience  may  be  designated,  in  cor- 
respondence to  the  two  ducts,  the  lobe  of  Wirsung  and 
the  lobe  of  Santorini.  They  are  separated  by  an  inter- 
lobular fissure  or  cleft  lying  midway  between  the  two 
ducts.  The  lobe  of  Santorini,  drawn  upward  in  the 
figure,  is  larger  than  the  lobe  of  Wirsung,  which  lies 
behind  it,  and  being  much  wider  from  above  down, 
forms  the  lower  or  descending  part  of  the  head  (Fig. 
7,  x).  The  lobe  of  Wirsung  is  a  relatively  narrow 
compressed  mass  of  parenchyma,  flattened  antero- 
posteriorly  and  surrounding  on  all  sides  the  duct  of 
Wirsung  ;  a  projection  (Fig.  7,  y),  before  mentioned, 
usually  passes  from  its  upper  and  left  aspect  behind 
the  superior  mesenteric  vessels. 


THE  ANATOMY  OF  THE  PANCREAS.      ^^ 

The  two  lobes  are  firmly  attached  to  the  duodenum 
in  the  neighborhood  of  their  respective  ducts,  but  be- 
tween the  ducts  each  lobe  is  readily  separable  fi-om 
the  intestine.  The  interlobular  fissure  where  it  is  in 
contact  with  the  duodenum  lies  midway  between  the  two 
ducts  in  a  direction  firom  above  downward  and  slightly 
forward,  and  extends  into  the  substance  of  the  head  a 
variable  distance,  often  four  to  five  centimetres,  its  depth 
being  dependent  upon  the  distance  from  the  duodenum 
at  which  the  two  ducts  anastomose.  Where  anastomosis 
has  occurred  near  the  orifice  of  one  duct  (Fig.  6,  iii.  and 
iv.),  the  other  duct  lengthening  during  the  course  of  sub- 
sequent development  becomes  much  bowed,  and  with 
it  the  corresponding  lobe,  so  that  the  interlobular  fissure 
can  be  followed  between  adjacent  surfaces  of  the  lobe, 
which  is,  as  it  were,  folded  upon  itself. 

After  breaking  through  the  loose  tissue  filling  the 
fissure,  adjacent  surfaces  of  the  two  lobes  are  found  to 
be  relatively  smooth  and  to  resemble  the  external  surface 
of  the  organ.  Within  the  fissure  are  contained  branches 
of  the  pancreatico-duodenal  artery  and  vein.  The 
common  bile  duct  usually  lies  along  the  upper  border  of 
the  lobe  of  Wirsung,  and  the  interlobular  cleft  meets 
the  upper  surface  of  the  gland  along  a  line  in  front  and 
to  the  left  of  this  duct.  In  order  to  expose  the  fissure, 
the  bile  duct  may  be  used  as  a  landmark. 

Relation  of  the  Common  Bile  Duct  to  the  Pancreas 
and  its  Ducts. — Study  of  the  diseases  of  the  liver  and 


33 


DISEASE    OF   THE   PANCREAS. 


of  the  pancreas  has  given  considerable  importance  to 
the  anatomical  relationship  of  the  bile  duct  to  the  pan- 
creas and  its  ducts.  The  common  bile  duct  descends 
towards  the  duodenum  alongside  the  head  of  the  pan- 
creas occasionally  embedded  in  its  substance,  and 
comes  in  contact  with  the  duct  of  Wirsung,  beside 
which  it  lies  for  a  short  but  variable  distance  before 
entering  the  wall  of  the  intestine. 

Helly  has  carefully  studied  the  relation  of  the  bile 
duct  to  the  head  of  the  pancreas  in  forty  cases.  The 
lower  part  of  the  duct  for  a  distance  varying  from  two 
to  seven  centimetres  is  in  contact  with  the  head  of  the 
pancreas,  or,  as  I  have  shown,  with  the  lobe  of  Wir- 
sung. In  fifteen  cases  (37.5  per  cent.)  the  duct  lay  in 
a  groove  upon  the  surface  of  the  gland  often  converted 
into  a  canal  by  the  adjacent  duodenum.  In  the  remaining 
twenty-five  cases  (62.5  per  cent.)  the  duct  was  completely 
surrounded  for  a  varying  distance  by  pancreatic  tissue. 

Embryological  study  has  shown  that  the  ventral 
pancreatic  outgrowth  of  the  intestine  arises  in  contact 
with  the  hepatic  duct,  while  the  dorsal  bud  arising 
at  an  earlier  period  is  situated  between  the  ductus 
hepaticus  and  what  will  subsequently  become  the 
stomach.  In  accordance  with  this  arrangement  the 
lower  pancreatic  duct,  the  duct  of  Wirsung,  in  all  the 
specimens  which  I  have  examined,  approaches  the  in- 
testine beside  the  bile  duct,  while  the  duct  of  Santorini 
enters  the  intestine  above  it.     Shirmer,  however,  states. 


THE  ANATOMY  OF  THE  PANCREAS.      39 

as  before  mentioned,  that  in  twelve  of  one  hundred  and 
four  cases  the  bile  duct  entered  the  intestine  in  com- 
pany with  the  upper  pancreatic  duct.  It  appears  not 
improbable  that  Shirmer  fell  into  error  in  the  examina- 
tion of  his  specimens. 

The  ductus  choledochus  and  the  duct  of  Wirsung 
penetrate  side  by  side  the  coats  of  the  duodenum, 
through  which  they  pass  obliquely  a  distance  of  about 
two  centimetres  and  cause  a  papilla-like  elevation  of 
the  mucous  membrane.  Within  the  papilla  they  unite 
to  form  a  short  common  cavity, — the  diverticulum  of 
Vater.  At  the  point  where  the  common  duct  enters  the 
wall  of  the  intestine  it  is  constricted,  or  at  least  but  little  dis- 
tensible, so  that  gall-stones  often  lodge  in  this  situation. 

The  description  of  the  diverticulum,  or  ampulla  of 
Vater,  given  by  different  anatomists  does  not  vary  ma- 
terially. It  may  be  described  as  a  conical  cavity  into 
the  base  of  which  open  the  two  ducts  ;  the  apex,  situ- 
ated at  the  summit  of  the  diverticulum,  is  their  common 
duodenal  orifice.  According  to  Testut,  its  length  varies 
from  six  to  seven  millimetres  ;  according  to  Sappey, 
from  seven  to  eight  millimetres.  Occasionally  the  two 
ducts  have  no  common  channel,  but  open  by  separate 
orifices  upon  the  summit  of  the  bile  papilla.  Claude 
Bernard  describes  a  mode  of  termination  which  has 
since  been  observed  by  others.  The  bile  duct  is  pro- 
longed as  far  as  the  mucosa  of  the  duodenum,  upon 
which  it  opens  by  a  circular  orifice.     The  terminal  part 


40  DISEASE   OF   THE   PANCREAS. 

of  the  pancreatic  duct,  like  a  gutter,  embraces  the  bile 
duct,  and  its  orifice  has  the  outline  of  a  crescent. 

The  orifice  of  the  diverticulum  of  Vater  constitutes  the 
narrowest  part  of  the  bile  channel,  and  here  small  cal- 
culi not  infrequently  become  impacted.  A  small  stone 
lodged  in  the  diverticulum  may  occlude  its  duodenal 
orifice,  and,  too  small  to  completely  fill  the  diverticulum 
and  occlude  the  two  ducts  that  enter  it,  may  convert 
the  latter  into  a  single  closed  channel  along  which  bile 
may  be  forced  by  the  gall-bladder  (Fig.  8,  i.).     Bile  thus 


a.e 


f 


dur 


Fig.  8. — Diagram  showing,  i.,  diverticulum  of  Vater  containing  a  calculus;  ii.,  common  bile  duct 
{dc.)  and  duct  of  Wirsung  (^dw)  entering  intestine  separately. 

injected  into  the  pancreatic  duct  causes,  as  will  be 
subsequently  shown,  the  condition  known  as  acute 
hemorrhagic  pancreatitis.  This  lesion  does  not  com- 
monly follow  the  expulsion  of  a  gall-stone  from  the 
common  duct.  For  its  production  it  is  necessary  that 
the  diverticulum  of  Vater  be  capacious,  with  a  length  at 
least  greater  than  the  diameter  of  its  duodenal  orifice. 

With  these  facts  in  view,  the  length  of  the  diverticu- 
lum has  been  measured  in  one  hundred  specimens  ;  vary- 


THE  ANATOMY  OF  THE  PANCREAS.      41 

ing-  from  zero  to  eleven  millimetres,  it  averages  only  3.9 
millimetres.  In  eleven  cases  the  two  ducts  open  sepa- 
rately at  the  summit  of  the  bile  papilla  and  no  diver- 
ticulum exists  (Fig.  8,  ii.).  In  only  thirty  instances  does 
the  length  of  the  diverticulum  reach  five  millimetres. 

In  seventy-five  of  these  specimens  the  diameter  of  the 
duodenal  orifice  has  been  measured  after  the  insertion 
of  probes  of  varying  size.  The  average  diameter  of 
the  orifice  is  2.5  millimetres.  In  twenty-one  cases  the 
diameter  of  the  orifice  is  equal  to  or  greater  than  the 
length  of  the  diverticulum  ;  and  it  is  obviously  impos- 
sible that  a  calculus,  assuming  it  to  be  approximately 
spherical  and  lodged  in  the  orifice,  could  only  par- 
tially occlude  the  cavity. 

Termination  of  the  Duct  of  Santormi. — The  termina- 
tion of  the  duct  of  Santorini  is  represented  upon  the 
mucosa  of  the  duodenum  by  an  elevated  papilla  situ- 
ated at  a  variable  distance  above  the  common  orifice  of 
the  duct  of  Wirsung  and  the  bile  duct  (see  Fig.  4). 
Though  often  small  and  inconspicuous,  it  is  recog- 
nized in  all  the  specimens  which  I  have  examined  ;  in 
one  case  it  is  so  small  that  it  has  been  found  only  after 
examination  of  serial  sections  through  the  mucosa  op- 
posite the  point  at  which  the  duct  of  Santorini  reached 
the  intestinal  wall.  The  papilla  varies  considerably  in 
size  and  shape,  being  at  times  a  small,  nipple-like  pro- 
jection, at  times  a  low,  broad  elevation.  Within  the 
papilla  the  duct  of  Santorini  usually  becomes  very  nar- 


42 


DISEASE    OF   THE   PANCREAS. 


row  and  is  not  infrequently  wholly  obliterated.  In 
serial  sections  it  is  found  irregular  in  outline,  provided 
with  many  lateral  diverticula,  and  often  very  tortuous. 

Much  difficulty  has  been  encountered  in  determining 
the  frequency  with  which  the  smaller  papilla  is  patent. 
On  the  one  hand  a  small  quantity  of  mucus  within  the 
minute  lumen  may  readily  prevent  the  penetration  of 
injected  material,  and  on  the  other  hand,  Henle  states, 
material  injected  under  considerable  pressure  may 
produce  a  false  passage.  By  injecting  air  into  the  duct 
Shirmer  was  unable  to  demonstrate  its  patency  in  twenty- 
one  of  one  hundred  and  four  specimens.  Helly  has  more 
recently  made  a  careful  microscopical  study  of  the  duct 
of  Santorini  as  it  penetrates  the  intestine,  and  in  ten  of 
fifty  specimens  found  it  obliterated. 

In  a  considerable  number  of  the  specimens  which  I 
have^  examined  it  was  not  possible  to  force  from  the 
lesser  papilla  fluid  injected  under  low  pressure  into  the 
duct  which  had  been  exposed  by  cutting  across  the 
body  of  the  gland.  Where  by  such  gross  exarriination  the 
patency  of  the  duct  of  Santorini  was  not  demonstrated, 
serial  sections  were  made  through  the  papilla,  and  in 
twenty-one  instances  the  lumen  of  the  duct  was  not 
found  demonstrably  continuous  with  that  of  the  intes- 
tine. Penetrating  the  muscularis  of  the  intestine  and 
passing  by  a  tortuous  course  a  variable  distance  into  the 
papilla,  the  duct,  beset  with  many  lateral  diverticula, 
ends  a  short  distance  below  the  mucosa  ;  the  duct  or  one 


THE  ANATOMY  OF  THE  PANCREAS.      43 

or  more  of  its  diverticula  approach  the  mucosa,  below 
which  there  is  occasionally  a  minute  dilatation. 

Helly  has  directed  attention  to  certain  microscopic 
peculiarities  of  the  lesser  papilla.  In  addition  to  the 
duct  the  papilla  contains  mucous  glands,  often  in  con- 
siderable number  ;  but  of  greater  interest  is  the  fact  that 
in  a  large  proportion  of  cases  (twenty-four  of  fifty 
instances)  the  papilla  contains  pancreatic  tissue  which 
is  either  wholly  separated  from  the  body  of  the  gland 
by  the  muscular  coat  of  the  intestine  or  is  distributed 
along  the  duct  as  it  penetrates  the  muscularis,  here 
lying  between  separated  muscle  bundles.  A  nodule  of 
considerable  size,  formed  by  numerous  lobules,  may  be 
situated  near  the  orifice  of  the  duct  immediately  below 
the  mucosa.  The  duct  of  this  pancreatic  tissue  does 
not  always  enter  the  duct  of  Santorini,  but  may  open 
independently  upon  the  overlying  mucosa  ;  the  nodule 
then  constitutes  a  true  accessory  pancreas. 

I  have  been  able  to  abundantly  confirm  the  observa- 
tions of  Helly,  and  in  thirty-five  specimens  in  which  the 
lesser  papilla  was  examined  to  determine  the  patency 
of  the  duct  of  Santorini,  pancreatic  tissue  was  absent 
in  only  six  instances.  A  compact  mass  of  normal 
pancreatic  tissue,  often  0.5  centimetre  across,  may 
lie  above  the  duct  of  Santorini  as  it  passes  obliquely 
through  the  submucosa  of  the  duodenum.  Occasion- 
ally individual  lobules  are  separated  by  coarse  bands  of 
connective  tissue,   while  not  infrequently  the  isolated 


44  DISEASE    OF   THE   PANCREAS. 

glandular  tissue  has  undergone  advanced  chronic  in- 
terstitial inflammation,  and  individual  acini,  having  an 
atrophied  appearance  and  separated  by  dense  con- 
nective tissue,  are  recognizable  only  by  comparison 
with  adjacent  less  changed  parenchyma. 

The  duct  which  drains  this  tissue  within  the  papilla 
usually  enters  the  duct  of  Santorini,  but  in  one  case  it 
was  demonstrated  by  serial  sections  to  open  inde- 
pendently into  the  duodenum.  In  one  instance  the 
duct  of  Santorini  did  not  penetrate  the  duodenal  mu- 
cosa, but  had  its  origin  in  small  branches  draining 
pancreatic  lobules  within  the  papilla. 

To  explain  the  occurrence  of  an  accessory  pancreas 
within  the  papilla  Helly  suggests  two  possibilities.  The 
isolated  bit  of  gland  tissue  may  arise  as  a  bud  nipped 
off  from  the  dorsal  embryonic  outgrowth  which  subse- 
quently forms  the  greater  part  of  the  pancreas  ;  wholly 
separated  from  the  main  mass,  its  ducts  later  form  an  in- 
dependent communication  with  the  duodenum.  Again, 
it  is  possible  that  the  dorsal  outgrowth  is  double,  as 
Stoss  and  Wlassow,  previously  cited,  have  claimed  ;  the 
accessory  tissue  might  in  that  case  constitute  a  persist- 
ent rudimentary  structure. 

In  a  later  publication  Helly  has  described  the  de- 
velopment of  the  lesser  pancreatic  papilla.  The  out- 
growth of  duodenal  epithelium  which  represents  the 
dorsal  rudiment  of  the  pancreas  penetrates  the  meso- 
blastic  part  of  the  intestinal  wall,  and  at  a  very  early 


THE  ANATOMY  OF  THE  PANCREAS.      45 

period  one  or  more  lateral  projections  or  buds  are 
formed  from  that  part  which  lies  in  the  intestinal  wall 
between  the  mucosa  and  the  muscularis.  From  this 
lateral  projection,  after  repeated  branching,  are  formed 
lobules  of  pancreatic  acini  lying  below  the  mucosa. 

Helly  has  never  found  pancreatic  tissue  surrounding 
the  duct  of  Wirsung  as  it  penetrates  the  duodenum, 
and  offers  an  explanation  of  its  absence.  The  duct  of 
Wirsung,  he  says,  in  most  cases  does  not  penetrate 
the  duodenum,  but  joins  the  ductus  choledochus  at  a 
variable  distance  from  its  termination.  At  the  period 
when  budding  from  the  duct  of  Santorini  first  occurs 
only  a  very  small  part  of  the  duct  of  Wirsung  lies  with- 
in the  intestinal  wall,  and  lateral  outgrowths  cannot 
penetrate  into  its  layers.  Occasionally,  as  already 
shown,  the  duct  of  Wirsung  may  penetrate  the  entire 
thickness  of  the  duodenum  ;  and  since  its  development 
then  resembles  that  of  the  duct  of  Santorini,  it  is  not  im- 
possible that  bits  of  pancreatic  tissue  be  included  in  the 
surrounding  intestinal  wall.  In  one  of  my  specimens, 
in  which  the  bile  papilla  was  very  large,  microscopic 
examination  demonstrated  the  presence  of  pancreatic 
lobules  surrounding  the  duct  of  Wirsung  as  it  ap- 
proached the  bile  duct  (see  accessory  pancreas.  Speci- 
men IX.  p.  54).  Helly  states  that  Pilliet  has  made  a 
similar  observation.  From  the  description  of  Pilliet  it 
appears,  however,  that  he  observed  mucous  glands,  but 
no  pancreatic  tissue,  about  the  ducts. 


CHAPTER    II. 

ANOMALIES    OF    THE    PANCREAS. 

Since  the  ducts  of  the  pancreas  are  subject  to  such 
great  variation,  it  is  not  surprising  that  the  gland  pre- 
sents anomalies  dependent  upon  alterations  of  the  usual 
process  of  development.  Malformations  have  been  de- 
scribed, particularly  by  earlier  writers.  The  tail  of  the 
gland  has  been  occasionally  found  to  be  bifid,  or  the 
absence  of  lobules  of  parenchyma  about  the  duct  for  a 
short  distance  has  caused  a  division  of  the  body  into 
two  parts.  Rarely  the  head  of  the  pancreas  completely 
surrounds  the  duodenum  and  may  cause  a  partial  con- 
striction of  its  lumen.  Shirmer  cites  from  the  older 
literature  instances  described  by  Tiedemann,  Becourt, 
Moyse,  Ecker,  and  more  recently  such  a  case  is  de- 
scribed by  Symington.  Tieken  has  reported  an  addi- 
tional example. 

That  part  of  the  gland  which  projects  behind  the  su- 
perior mesenteric  artery  has  been  designated,  pancreas 
parvum  of  Winslow.  Though  at  times  well  defined  by 
a  deep  cleft,  it  is  not  isolated  from  the  remainder  of  the 
gland,  and  its  duct  joins  the  duct  of  Wirsung. 

Accessory  Pancreas. — Of  greater  interest  is  the  oc- 
currence of  an  accessory  pancreas, — a  mass  of  pan- 
46 


ANOMALIES   OF   THE   PANCREAS.  47 

creatic  tissue  situated  in  the  wall  of  the  intestine, 
wholly  separated  from  the  pancreas,  and  provided  with 
a  duct  of  its  own.  Klob  first  demonstrated  the  exist- 
ence of  such  isolated  masses  of  pancreatic  tissue  and 
described  two  examples  of  this  anomaly.  In  one  in- 
stance a  small  flattened  glandular  mass  was  embedded 
in  the  wall  of  the  stomach,  near  the  mid-part  of  its 
greater  curvature  ;  in  the  second  case  a  similar  tumor- 
like body  occupied  the  wall  of  the  jejunum  four  inches 
from  the  duodenum. 

Zenker  subsequently  collected  six  examples  of  the 
anomaly,  and  in  every  case  demonstrated  the  existence 
of  a  duct  entering  the  intestine  through  the  overlying 
mucosa.  These  accessory  glands  were  situated  in 
various  parts  of  the  small  intestine.  One  occurred 
between  the  pyloric  orifice  of  the  stomach  and  the  pan- 
creas, while  three  were  found  in  the  upper  part  of  the 
jejunum  near  the  duodenum.  In  one  case  two  acces- 
sory bodies  were  present  in  the  jejunum,  one  sixteen 
centimetres,  the  other  forty-eight  centimetres  below  the 
duodenum.  Of  especial  interest  is  the  sixth  case,  in 
which  at  the  summit  of  a  finger-shaped  diverticulum  of 
the  ileum,  5.5  centimetres  in  length,  situated  fifty-four 
centimetres  from  the  ileo-csecal  valve,  was  a  small  acces- 
sory pancreas,  of  which  the  duct  opened  into  the  diver- 
ticulum. The  relation  of  these  bodies  to  the  coats  of 
the  intestine  varied.  In  three  instances,  including  two 
present   in   the   same    individual,  the    accessory  gland 


48  DISEASE    OF    THE   PANCREAS. 

lay  in  the  submucosa  ;  in  three  cases  the  chief  mass 
was  within  the  macularis  ;  while  in  the  sixth  case  the 
pancreatic  tissue  occupied  both  submucous  and  mus- 
cular layers.  Microscopic  examination  showed  that 
the  component  tissue  resembled  that  of  the  pancreas, 
save  that  the  interlobular  connective  tissue  was  fre- 
quently more  abundant  than  usual.  Zenker  thinks 
that  these  bodies  represent  a  congenital  anomaly  of 
development  referable  to  the  existence  of  an  accessory 
embryonic  rudiment  which,  though  at  first  in  imme- 
diate proximity  to  the  pancreas,  is  by  the  subsequent 
lengthening  of  the  gastro-intestinal  tract  carried  to  a 
varying  distance  either  above  or  below  the  gland. 

A  few  additional  examples  of  aberrant  pancreas 
have  been  recorded.  Wagner  has  described  two  such 
bodies,  one  in  the  intestine,  the  other  in  the  submucosa 
of  the  anterior  wall  of  the  stomach  near  the  lesser 
curvature  and  midway  between  cardiac  and  pyloric  ori- 
fices. Gegenbaur  found  an  accessory  pancreas  in  the 
submucosa  of  the  stomach  near  the  pylorus.  Upon  the 
intestine  of  a  child  ten  months  old  Neumann  observed, 
sixty  centimetres  above  the  ileo-csecal  valve,  a  diver- 
ticulum three  centimetres  in  length,  upon  the  summit 
of  which  was  situated  a  pea-sized  body  having  the 
structure  of  pancreatic  tissue  and  provided  with  a  duct 
entering  the  diverticulum. 

Attached  to  the  ileum  of  an  adult  man,  Nauwerk 
found  a  slender  appendage  nine  centimetres  in  length. 


ANOMALIES    OF   THE    PANCREAS.  49 

2.3  metres  above  the  ileo-caecal  valve.  It  consisted 
of  a  small  mass  of  pancreatic  tissue  attached  to  the 
summit  of  a  funnel-shaped  diverticulum  ;  a  small  duct 
entered  the  diverticulum.  Hansemann  has  added 
another  example,  and  Shirmer  has  described  a  simi- 
lar diverticulum  surmounted  by  an  accessory  pancreas 
and  situated  one  hundred  and  fifteen  centimetres  above 
the  ileo-caecal  valve.  In  a  second  case  of  Shirmer  an 
accessory  pancreas  occupied  the  submucosa  and  mus- 
cularis  of  the  stomach  a  short  distance  from  the  pylorus, 
Glinski  has  described  an  accessory  gland  of  large  size, 
4.5  by  3.5  centimetres  across  and  one  centimetre  in 
thickness,  situated  in  the  muscularis  of  the  posterior 
wall  of  the  stomach  near  the  pylorus.  In  two  hundred 
autopsies  Letulle  found  in  as  many  as  five  cases  aber- 
rant glands,  and  describes  a  sixth  case  in  which  a  par- 
tially isolated  mass  of  pancreatic  tissue  formed  part  of 
the  head  of  the  pancreas. 

Wright  has  described  an  unique  example  of  the 
anomaly.  A  child  twelve  years  of  age  had  suffered 
with  a  congenital  umbilical  fistula.  The  fistulous  tract 
was  removed,  and  within  the  tissue  was  embedded  a 
nodule  3.5  millimetres  in  diameter,  composed  of  glan- 
dular acini  identical  with  those  of  the  pancreas  and 
containing  readily  recognizable  islands  of  Langerhans. 

Altogether  twenty-two  instances  of  this  anomaly  have 
been  described.  The  following  ten  examples  collected 
from  eighteen  hundred  autopsies  present  features  which 


50  DISEASE   OF   THE   PANCREAS. 

I  believe  explain  their  process  of  development,  and  for 
this  reason  are  described  with  some  detail.  For  the 
sake  of  convenience  they  may  be  divided  into  two 
groups, — those  situated  above  the  pancreas  in  the 
stomach  and  duodenum  and  those  below  the  gland  in 
the  duodenum  and  jejunum. 

Accessory  Gland  above  the  Pancreas. 

Specimen  I. — Accessory  pancreas  of  the  stomach  in  a  white  man, 
aged  forty  years.  Near  the  lesser  curvature  of  the  stomach,  eight 
centimetres  from  the  pylorus,  is  a  firm  flattened  nodule,  i .  2  centi- 
metres across,  lying  below  the  mucosa  and  projecting  slightly  upon 
the  peritoneal  surface,  which  has  over  it  an  irregular  nodular  appear- 
ance. Microscopic  examination  shows  a  compact  mass  of  tissue 
identical  in  structure  with  that  of  the  pancreas,  situated  in  the  sub- 
mucosa  and  extending  into  the  muscularis,  of  which  the  muscle  bundles 
are  separated  and  much  distorted  by  the  presence  of  numerous  scat- 
tered lobules  of  glandular  tissue.  Between  the  lobules,  and  at  times 
within  them,  particularly  in  the  submucosa,  connective  tissue  is  more 
abundant  than  in  the  normal  pancreas.  Ducts  of  considerable  size 
are  present  but  are  not  dilated. 

Specimen  II. — Accessory  pancreas  of  the  stotnach  in  a  colored 
boy,  aged  eleven  years.  Below  the  mucous  membrane  of  the  stomach, 
two  centimetres  from  the  pylorus,  is  a  firm  nodule  five  millimetres 
in  diameter.  Microscopic  examination  shows  a  small  mass  of  pan- 
creatic tissue  situated  in  the  submucosa.  Fibrous  stroma  is  some- 
what more  abundant  between  the  lobules  than  in  the  normal  gland. 
Slightly  dilated  ducts  lined  by  high  columnar  epithelium  are  most 
numerous  and  largest  near  the  surface  of  the  nodule  next  to  the  mus- 
cular coat  of  the  stomach. 

Specimen   III. — Aberra?it  pancreas  of  the  pylorus  in  a  woman, 


ANOMALIES    OF   THE   PANCREAS.  51 

aged  sixty-five  years.  At  the  site  of  the  pyloric  valve  of  the  stomach, 
projecting  into  the  lumen,  is  an  elevation  of  the  mucosa,  caused,  as 
microscopic  examination  shows,  by  a  nodule  of  pancreatic  tissue 
situated  in  the  submucosa ;  in  the  sections  examined  are  found  two 
islands  of  Langerhans,  structures  peculiar  to  the  pancreatic  paren- 
chyma. Numerous  dilated  ducts  are  present,  and  are  most  numerous 
near  the  muscularis.  In  the  underlying  muscle  of  the  pylorus  is 
found  a  group  of  small  ducts,  while  immediately  below  the  serosa  are 
on  section  two  widely-dilated,  duct-like  channels  lined  by  high  colum- 
nal  cells. 

Specimen  IV. — Accessory  pancreas  of  the  stomach  and  nodule  of 
the  pylorus  containing  dilated  ducts  in  a  white  man,  aged  seventy 
years.  In  the  wall  of  the  stomach,  eight  centimetres  from  ^e  pylorus, 
is  a  nodule  composed  of  a  gland-like  tissue,  two  centimetres  across, 
projecting  upon  both  the  mucous  and  serous  surfaces.  At  the  pylorus 
is  a  second  nodule-like  projection  of  the  mucosa,  about  seven  milli- 
metres across ;  but  here  on  section  no  gland-like  tissue  is  found. 
Examination  of  the  pancreas  demonstrates  the  existence  of  two  ducts, 
of  which  the  duct  of  Santorini  is  smaller  and  terminates  in  a  small 
papilla.  At  the  site  of  the  bile  papilla  is  a  short  diverticulum  of  the 
mucous  membrane.  Microscopic  examination  of  the  gastric  nodule 
shows  partly  in  the  submucosa  but  chiefly  in  the  muscularis,  sepa- 
rating its  muscle  bundles,  pancreatic  lobules  and  groups  of  lobules 
which  often  contain  much  interstitial  tissue,  as  though  the  seat  of 
chronic  interstitial  inflammation.  Islands  of  Langerhans  are  fairly 
abundant,  and  ducts,  often  with  wide  lumina,  occur  throughout  the 
section.  The  papillary  projection  at  the  pylorus  is  produced  by  an 
increase  in  the  thickness  of  the  submucosa,  where,  surrounded  by  a 
quantity  of  connective  tissue,  is  found  cut  transversely  a  duct-like 
structure  lined  by  columnar  epithelium  and  identical  in  appearance 
with  the  ducts  of  the  pancreatic  nodule.  In  the  underlying  muscle 
of  the  pylorus  several  ducts  of  larger  size  are  cut  across,  while  imme- 


52  DISEASE    OF   THE   PANCREAS. 

diately  below  the  serosa  the  section  cuts  twice  what  appears  to  be  a 
dilated  tortuous  duct. 

Specimen  V. — Aberrant  pancreas  {x^  of  the  stomach  and  {2.^  of 
the  duodenum,  together  with  pancreatic  tissue  in  the  lesser  papilla  in 
a  white  boy,  aged  four  years.  Immediately  below  the  mucous  mem- 
brane of  the  stomach,  only  two  millimetres  from  the  pyloric  orifice, 
is  a  nodule  of  gland-like  tissue  three  millimetres  across.  Below  the 
mucosa  of  the  duodenum,  9.5  centimetres  below  the  pylorus,  is  a 
second  nodule  of  similar  character,  about  seven  millimetres  across. 
The  papilla  of  the  duct  of  Santorini  is  represented  by  a  hemi- 
spherical elevation,  seven  millimetres  across,  which  on  section  appears 
to  contain  a  third  isolated  nodule  of  glandular  tissue.  Microscopic 
examination  shows  that  the  nodule  of  pancreatic  tissue  situated  in  the 
submucosa  of  the  stomach  has  been  the  seat  of  moderate  chronic 
interstitial  inflammation,  and  its  ducts,  which  converge  towards  its 
under  surface,  are  dilated  and  contain  polynuclear  leucocytes  ;  islands 
of  Langerhans  occur.  The  duodenal  nodule  immediately  below  the 
pylorus  consists  of  pancreatic  tissue  situated  in  the  submucosa  and 
muscularis,  of  which  the  bundles  are  split  apart  and  distorted.  It 
projects  beyond  the  muscle  upon  the  outer  surface  of  the  intestine. 
Ducts  and  islands  of  Langerhans  occur.  In  the  submucosa, 
immediately  above  the  duct  of  Santorini,  after  it  has  penetrated 
the  muscularis  of  the  duodenum,  is  situated  a  third  nodule  of 
pancreatic  substance,  adding  considerably  to  the  size  of  the 
papilla. 

Specimen  VI. — Aberrant  pancreas  of  the  duodenum  together  with 
pancreatic  tissue  in  the  lesser  papilla.  The  mucous  membrane  of  the 
duodenum,  four  centimetres  above  the  papilla  of  the  duct  of  Santo- 
rini, presents  a  low  elevation  seven  millimetres  across.  The  papilla 
of  the  duct  is  represented  by  a  low,  broad  elevation  five  millimetres 
across;  the  duct  of  Santorini,  smaller  than  the  duct  of  Wirsung, 
joins  the  latter  and  is  patent  throughout.     The  nodular  elevation  of 


ANOMALIES   OF   THE   PANCREAS.  53 

the  duodenum  is  by  microscopic  examination  shown  to  be  caused  by 
the  presence  of  numerous  pancreatic  lobules  and  groups  of  lobules 
situated  between  separated  bundles  of  the  muscularis.  A  few  lobules 
which  are  the  seat  of  chronic  interstitial  inflammation  are  situated 
in  the  submucosa,  through  which  a  tortuous  duct  surrounded  by 
numerous  diverticula  and  abundant  connective  tissue  can  be  traced 
to  the  surface  of  the  mucosa.  The  lesser  papilla  of  the  pancreas  is 
on  microscopical  examination  found  to  contain  a  few  lobules  of 
pancreatic  tissue  which  has  undergone  chronic  interstitial  inflam- 
mation. 

Specimen  VII. — Aberrant  pancreas  of  the  duodenum  in  a  woman, 
aged  fifty-six  years.  Projecting  upon  the  external  surface  of  the  du- 
odenum, between  the  stomach  and  the  pancreas,  is  a  hemispherical 
nodule  eight  millimetres  across,  which  on  opening  the  duodenum  is 
found  to  cause  a  slight  elevation  of  the  mucosa.  On  microscopic 
examination  the  main  mass  of  the  nodule  is  found  to  project  outside 
the  muscle  coats,  which  are  split  apart  and  over  a  considerable  area 
broken  through,  so  that  the  nodule  is  continuous  with  a  smaller  col- 
lection of  pancreatic  lobules  which  have  undergone  chronic  intersti- 
tial inflammation  and  are  situated  in  the  submucosa.  Ducts  are 
present  and  islands  of  Langerhans  occur. 

Accessory  Gland  below  the  Pancreas. 

Specimen  VIII. — Accessory  pancreas  of  the  duodenum  in  a  white 
woman,  aged  forty  years.  A  small  nodule  of  grayish -yellow  tissue 
situated  in  the  wall  of  the  duodenum  below  the  pancreas  causes  an 
elevation  of  both  the  raucous  and  serous  surfaces.  Microscopic  ex- 
amination shows  that  a  mass  of  pancreatic  tissue  is  situated  in  the 
submucosa,  and  extending  through  the  circular  muscle  coat,  separates 
the  latter  from  the  longitudinal  layer.  Dense  stroma  surrounds  and 
often  invades  the  gland  lobules.  Ducts  lined  by  columnar  epithelium 
occur. 


54 


DISEASE    OF   THE    PANCREAS. 


Specimen  IX. — Accessory  pancreas  of  the  jejunum  showing  ad- 
vanced chronic  interstitial  infl.a?n?nation  together  with  pancreatic  tis- 
sue in  the  bile  papilla  in  a  colored  woman,  aged  fifty -nine  years.  In 
the  jejunum,  one  hundred  and  eleven  centimetres  below  the  duo- 
denum, is  an  oval  elevation  of  the  mucosa  i .  5  centimetres  in  length, 
situated  opposite  the  mesentery  and  caused  by  an  underlying  nodule 
of  fimi  grayish  tissue  containing  minute  cysts.  Microscopically  the 
tissue  resembles  at  first  sight  a  small  adenoma,  since  embedded  in 
dense  fibrous  stroma  are  groups  of  gland-like  structures  formed  by 
high  columnar  cells  surrounding  a  wide  lumen.  In  the  centre  of 
each  group  are  one  or  more  larger,  irregularly  tubular  structures 
resembling  ducts,  while  embedded  in  the  dense  stroma  occur 
glandular  acini,  which  are  readily  identified  with  those  of  the  pan- 
creas, since  they  contain  centro-acinar  cells.  The  main  mass  of  the 
nodule,  which  has  undergone  advanced  chronic  intestinal  inflamma- 
tion, is  situated  in  the  subraucosa,  but  bundles  of  the  underlying 
circular  muscle  are  separated  and  distorted  by  the  presence  of  dilated 
ducts.  The  duct  of  Wirsung  of  the  pancreas  is  much  smaller  than 
the  duct  of  Santorini,  and  does  not  anastomose  with  it.  The  bile 
papilla  is  of  very  large  size,  and  examined  microscopically  is  found 
to  contain  lobules  of  pancreatic  tissue,  adding  considerably  to  its 
bulk.  They  surround  the  duct  before  it  enters  the  diverticulum  of 
Vater,  which  is  only  2.5  millimetres  in  length. 

Specimen  X. — Accessory  pancreas  of  the  jejwiiim  showing  ad- 
vanced chronic  interstitial  infia77i7nation  and  resembli7ig  a  S77iall 
adeno7)ia  in  a  white  man,  aged  thirty-eight  years.  In  the  jejunum, 
four  metres  from  the  stomach,  is  an  elevation  of  the  mucosa  caused 
by  an  underlying  nodule  of  tissue  about  one  centimetre  across.  Mi- 
croscopic examination  shows  numerous  ducts,  isolated  or  surrounded 
by  mucous  glands  and  identical  in  appearance  with  those  of  the  pan- 
creas. They  are  embedded  in  abundant  dense  fibrous  stroma,  and 
the  appearance  agrees  with  that  of  Specimen  IX.,  save  that  lobules 


ANOMALIES   OF   THE    PANCREAS. 


55 


of  pancreatic  acini  are  no  longer  preserved.     The  nodule  is  situated 
wholly  in  the  submucosa. 

In  the  cases  just  described  small  masses  of  pan- 
creatic tissue,  usually  not  more  than  a  centimetre 
across,  have  been  found  in  the  stomach,  in  the  duo- 
denum, in  the  jejunum,  and  even  in  the  ileum.  Rarely 
are  two  accessory  glands  found  in  the  same  individual. 
In  a  case  described  by  Zenker  two  nodules  were  found 
in  the  jejunum.  In  Specimen  IV.  of  the  present  series 
a  second  nodule  situated  at  the  pylorus,  though  con- 
taining only  dilated  ducts,  doubtless  represents  a 
second  isolated  remnant  of  pancreatic  tissue  ;  in  Speci- 
men V.  two  bodies  occur,  one  in  the  stomach,  the  other 
in  the  duodenum. 

In  twenty-six  cases,  including  those  just  described, 
and  excluding  one  of  Wright,  which  was  without 
autopsy,  one  of  Wagner,  and  five  of  Letulle,  in 
which  the  location  is  not  definitely  stated,  the  dis- 
tribution of  twenty-nine  accessory  bodies  was  as  fol- 
lows : 

Above  the  pancreas  : 

Stomach,  ii. 

Duodenum,  4. 
Below  the  pancreas : 

Duodenum,  i. 

Jejunum,  9. 

Ileum,  4. 


56  DISEASE   OF   THE    PANCREAS. 

The  situation  of  the  accessory  pancreatic  tissue  with 
relation  to  the  coats  of  the  intestine  varies  slightly.  It 
is  usually  situated  in  the  muscularis  of  which  the 
muscle  bundles  are  separated  and  distorted  by  the 
presence  of  pancreatic  lobules  and  groups  of  lobules, 
and,  it  will  be  shown  later,  the  muscular  coat  may 
be  much  weakened  by  the  presence  of  the  glandular 
tissue.  In  three  of  the  cases  which  I  have  observed 
the  aberrant  gland,  was  situated  wholly  in  the  sub- 
mucosa,  while  in  four  additional  instances,  though 
no  glandular  lobules  were  present  in  the  underlying 
muscle  layer,  ducts  were  here  found.  In  the  remaining 
instances  the  body  occupied  the  muscular  layer. 

The  tissue  of  the  aberrant  gland  does  not  differ  in  its 
histological  features  from  that  of  the  pancreas.  Nu- 
merous ducts  occur,  and  doubtless  open  on  the  intes- 
tinal mucosa,  though  this  fact  was  demonstrated  by 
serial  sections  in  one  instance  only.  Within  the  acini 
are  found  centro-acinar  cells.  Letulle  states  that  the 
peculiar  bodies  known  as  islands  of  Langerhans  do 
not  occur  in  the  accessory  gland.  Wright  has,  how- 
ever, demonstrated  their  presence  in  a  pancreatic  nod- 
ule removed  from  the  neighborhood  of  the  umbilicus, 
and  in  five  of  my  cases  they  have  been  found. 

The  isolated  nodule  of  pancreatic  tissue  tends  to 
undergo  chronic  interstitial  inflammation,  and  inter- 
stitial tissue  is  almost  constantly  present  in  greater 
quantity   than    in    the    normal    gland.       Inflammatory 


ANOMALIES    OF   THE    PANCREAS.  57 

changes  are  probably  dependent  upon  occlusion  of  the 
minute,  often  tortuous,  ducts,  and  are  doubtless  intensi- 
fied by  the  invasion  of  bacteria  from  the  intestine  or 
stomach.  The  ducts  are  frequently  dilated,  and  in  one 
instance  (Specimen  IV.)  some  of  them  contain  poly- 
nuclear  leucocytes.  In  two  nodules,  situated  in  the 
jejunum,  chronic  inflammation  has  reached  an  advanced 
stage,  and  one  nodule  consists  in  great  part  of  fibrous 
tissue  and  dilated  ducts,  surrounded  by  hypertrophied 
mucous  glands,  while  in  the  other  the  pancreatic  acini 
have  undergone  complete  destruction.  In  such  cases 
the  nodules  resemble  small  adenomata. 

Origin  of  the  Accessory  Pancreas. — The  origin  of 
the  accessory  bodies  under  consideration  is  of  much 
interest.  Zenker  thought  that  they  are  referable  to 
the  occurrence  of  an  abnormal  pancreatic  rudiment  or 
"  anlage"  which,  formed  in  close  proximity  to  the  prim- 
itive pancreatic  outgrowth  of  the  intestinal  tract,  is  sub- 
sequently separated  from  it  by  the  longitudinal  growth 
of  the  intestinal  wall.  Arising  before  the  stomach  is 
distinct  from  the  duodenum,  the  accessory  body,  carried 
upward,  may  finally  occupy  the  gastric  wall,  while  if 
situated  below  the  pancreas  it  would  be  transported 
in  the  direction  of  the  ileo-caecal  valve. 

To  explain  the  occurrence  of  these  bodies,  Glinski 
directs  attention  to  the  development  of  the  pancreas 
from  more  than  one  rudimentary  outgrowth  of  the 
intestine.     Most  recent  observers,  as  before  mentioned, 


58  DISEASE    OF   THE    PANCREAS. 

have  described  one  dorsal  and  two  ventral  diverticula. 
Since  the  pancreas  of  individuals  possessing  an  acces- 
sory gland  has  not  been  found  to  be  abnormal,  Glinski 
assumes  that  its  development  proceeds  normally  from 
two  primitive  intestinal  diverticula.  The  additional 
rudimentary  outgrowth  persisting  may,  Glinski  believes, 
give  rise  to  an  accessory  nodule  subsequently  carried 
above  or  below  the  main  glandular  mass  by  growth 
of  the  intestine.  In  order  to  explain  the  existence  of 
two  accessory  glands,  as  in  the  case  of  Zenker,  it  is 
necessary  to  assume  the  existence  of  four  original 
"anlage,"  the  dorsal  embryonic  outgrowths  in  such 
case  being  double. 

The  orifice  of  the  duct  of  Santorini,  which  represents 
the  dorsal  embryonic  outgrowth,  has  been  found  in  one 
hundred  subjects  which  I  have  examined  to  be  con- 
stantly situated  above  (nearer  the  stomach)  the  duct  of 
Wirsung,  which  represents  the  ventral  outgrowth,  and 
is  always  in  contact  with  the  common  bile  duct.  Should 
an  accessory  pancreas  arise  by  persistence  of  one  of  the 
two  ventral  outgrowths,  subsequent  lengthening  of  the 
intestine  should  carry  it  in  only  one  direction, — namely, 
towards  the  jejunum  ;  while  should  it  arise  from  part  of 
a  double  dorsal  outgrowth,  as  Ghnski  suggests,  it  would 
be  transported  upward  in  the  direction  of  the  stomach. 
The  occurrence  of  two  aberrant  glands  above  the 
pancreas,  as  in  Specimens  Y.  and  VI.,  would  then  be 
explicable  only  by  assuming  the  occasional  occurrence 


ANOMALIES    OF   THE    PANCREAS.  59 

of  a  triple  primitive  dorsal  rudiment,  since,  at  least 
in  the  cases  which  I  have  described,  both  pancreatic 
ducts  had  developed  normally.  Such  a  condition  has 
not  been  found  in  any  vertebrate  species. 

Helly  has  shown  that  a  small  mass  of  pancreatic 
tissue  may  occur  in  the  papilla  of  the  duct  of  Santorini 
wholly  separated  from  the  remainder  of  the  gland. 
Its  duct  may  enter  the  duct  of  Santorini,  or  the  isolated 
tissue  constituting-  a  true  accessory  gland  may  be  pro- 
vided with  a  duct  opening  independently  into  the  duo- 
denum. In  the  latter  case  Helly  suggests  two  possi- 
bilities:  the  embryonic  dorsal  "anlage"  is  double,  or 
a  part  of  the  primitive  outgrowth  is  separated  from 
the  remainder  and  later  acquires  an  independent  duct. 
Helly's  subsequent  study  of  the  embryonic  develop- 
ment of  the  papilla  (cited  on  page  44)  supports  the 
latter  hypothesis.  At  an  early  period  of  development 
lateral  branches  of  the  dorsal  pancreatic  outgrowth 
penetrate  the  submucosa  or  muscularis  of  the  intes- 
tine, ultimately  forming  the  lobules  which  surround  the 
duct  as  it  passes  obliquely  through  the  intestinal  wall. 
Should  the  duct  draining  these  lobules  be  occluded  by 
the  development  of  adjacent  muscle  bundles  or  fibrous 
tissue,  it  is  by  no  means  inconceivable  that  a  new  duct 
might  be  established, — for  it  has  long  been  known  that 
the  pancreatic  duct  after  section  or  ligation  regenerates 
and  re-establishes  its  lumen.  This  fact  was  known  to 
Claude  Bernard.    Pawlow  and  Smirnow  have  described 


6o  DISEASE    OF    THE    PANCREAS. 

in  detail  an  experiment  upon  a  rabbit  in  which  two 
months  after  ligating  the  pancreatic  duct  a  new  channel 
entering  the  duodenum  was  found  beside  the  ligature. 
Ssobolew,  among  others,  has  noted  similar  regeneration 
of  the  duct. 

Should  one  or  more  embryonic  buds  of  glandular  tissue 
make  their  way  into  the  wall  of  the  intestine  at  an  early 
period,  they  might  be  carried  from  the  remainder  of 
the  gland  by  the  longitudinal  growth  of  the  intestine  ; 
arising  from  the  dorsal  pancreatic  outgrowth  which  is 
situated  above  the  ventral,  the  aberrant  tissue  would  be 
carried  towards  the  stomach  ;  if  from  the  ventral  out- 
growth, towards  the  jejunum.  The  existence  of  more 
than  one  accessory  body  above  or  below  the  pancreas 
is  then  explicable  without  assuming  the  occurrence  of  an 
embryonic  condition  unknown  among  the  vertebrates. 

In  accordance  with  this  conception,  accessory  bodies 
are  formed  by  a  process  similar  to  that  which  so  fre- 
quently isolates  a  bit  of  pancreatic  substance  in  the 
papilla  of  the  duct  of  Santorini ;  and  in  the  cases  where 
an  examination  was  made,  pancreatic  tissue  was  found 
in  the  lesser  or  greater  papilla  when  an  accessory 
nodule  occurred  above  or  below  the  pancreas.  In 
Specimens  V.  and  VI.  the  papilla  of  the  duct  of  Santo- 
rini was  examined  microscopically  and  found  to  contain 
lobules  of  pancreatic  tissue.  In  Specimen  V.,  in  which  an 
aberrant  pancreas  occurred  in  the  stomach  and  another 
in   the   duodenum   immediately  below  the  pylorus,  the 


ANOMALIES   OF   THE    PANCREAS.  6 1 

papilla  of  the  duct  of  Santorini  contained  a  third  isolated 
nodule  of  pancreatic  tissue.  Of  greater  import  is 
Specimen  IX.,  in  which  an  accessory  body  occurred  in 
the  jejunum  ;  here  the  bile  papilla  contained  lobules  of 
pancreatic  acini — a  condition  never  observed  by  Helly. 
If  an  accessory  body  arises  from  the  ventral  embryonic 
outgrowth  at  a  time  when  the  distance  between  the 
hepatic  duct  and  the  umbilical  stalk  is  slight,  subse- 
quent growth  of  the  intestine  will  locate  it  at  some 
point  between  these  structures.  Wright  has  reported 
an  unique  case  in  which  a  nodule  of  pancreatic  tissue 
was  removed  from  the  neighborhood  of  the  umbilicus 
during  life. 

The  results  of  the  preceding  study  may  be  sum- 
marized as  follows :  The  duct  of  Santorini,  as  it  pene- 
trates the  duodenal  wall,  is  in  almost  all  individuals 
partially  surrounded  by  lobules  of  pancreatic  tissue 
lying  between  separated  muscle  bundles  or  forming  a 
more  or  less  compact  mass  within  the  lesser  papilla. 
The  duct  which  drains  this  tissue  usually  enters  the 
duct  of  Santorini,  but  occasionally  opens  independently 
into  the  duodenum.  This  pancreatic  tissue  within  the 
intestinal  wall  frequently  undergoes  chronic  interstitial 
inflammation  and  may  partially  disappear.  The  duct  of 
Wirsung  within  the  bile  papilla  is  more  rarely  accom- 
panied by  lobules  of  pancreatic  tissue. 

Accessory  nodules  of  pancreatic  tissue  are  not  infre- 


62  DISEASE   OF   THE   PANCREAS. 

quently  found  embedded  within  the  wall  of  the  gastro- 
intestinal tract  from  the  pyloric  region  of  the  stomach 
to  the  ileum.  In  most  instances  they  are  in  part  or 
wholly  situated  in  the  muscular  layer.  The  glandular 
tissue  of  which  they  are  composed  does  not  differ  in 
histological  structure  from  that  which  forms  the  pan- 
creas and  contains  characteristic  islands  of  Langerhans. 
It  tends  to  undergo  chronic  interstitial  inflammation. 

The  aberrant  pancreas  and  the  isolated  tissue  within 
the  duodenal  papilla  owe  their  origin  to  the  same 
process.  At  a  very  early  period  of  embryonic  develop- 
ment lateral  branches  bud  from  the  rudimentary  pan- 
creatic ducts  as  they  penetrate  the  mesoblastic  layers 
of  the  intestinal  canal ;  from  these  branches  is  formed 
the  pancreatic  tissue  of  the  papilla.  A  small  mass  of 
glandular  parenchyma  entangled  in  the  fibrous  or  mus- 
cular tissue  of  the  embryonic  wall  may  be  carried 
by  subsequent  longitudinal  growth  of  the  intestine  a 
variable  distance  above  or  below  the  pancreas,  thus 
forming  an  accessory  gland. 

Diverticula  of  the  Intestine  Resulting  from  Anoma- 
lies of  the  Pancreas. — Among  recorded  instances  of  ac- 
cessory pancreas  are  several  associated  with  diverticula 
of  the  intestine.  In  one  case  of  Zenker  a  nodule  of 
pancreatic  tissue  was  situated  at  the  summit  of  a  diver- 
ticulum of  the  ileum  5.5  centimetres  in  length  and  fifty- 
four  centimetres  from  the  ileo-caecal  valve.  Neumann 
found    in    a  child    ten    months  of   age  a   diverticulum 


ANOMALIES   OF   THE   PANCREAS.  6^ 

situated  sixty  centimetres  from  the  valve  and  capped 
by  an  accessory  pancreas  the  size  of  a  pea.  In  a  case 
of  Nauwerk  a  small  mass  of  pancreatic  tissue  was 
located  at  the  apex  of  a  funnel-shaped  intestinal  diver- 
ticulum 2.3  metres  from  the  valve.  Hansemann  states 
that  he  has  seen  an  accessory  pancreas  attached  to  the 
summit  of  a  diverticulum  of  the  jejunum. 

Zenker  thought  that  the  diverticulum  which  he  de- 
scribed was  the  remains  of  the  vitelline  duct  and  rep- 
resented the  so-called  Meckel's  diverticulum.  Since 
the  pancreas  begins  its  development  at  a  period  when 
the  vitelline  duct  is  already  formed,  Neumann  did  not 
think  the  accessory  pancreatic  nodule  could  occupy  the 
summit  of  a  diverticulum  formed  from  that  structure. 
Nauwerk  has  confirmed  this  view,  for  in  his  case  a  true 
Meckel's  diverticulum  occupied  the  wall  of  the  jleum 
between  the  ileo-csecal  valve  and  diverticulum  upon 
which  was  situated  an  aberrant  pancreas.  The  forma- 
tion of  a  diverticulum  accompanying  the  accessory 
gland  is  thought  by  Neumann,  Nauwerk,  and  Hanse- 
mann to  be  the  result  of  traction  exerted  by  the  aber- 
rant nodule. 

Accessory  pancreatic  tissue,  it  has  been  shown  above, 
is  usually  situated  in  the  muscular  layer  of  the  intes- 
tine, separating  and  distorting  the  muscular  bundles 
and  at  times  (Specimen  VII.)  causing  a  defect  in  the 
muscle  coat.  Pressure  within  the  intestine  during  peri- 
stalsis doubtless   causes    a  hernial    protrusion  of    the 


64  DISEASE   OF   THE    PANCREAS. 

mucosa  and  submucosa  through  the  weakened  muscu- 
laris.  It  appears  improbable  that  the  small  nodule  of 
tissue  exerts  appreciable  attraction  upon  the  intestinal 
wall. 

Diverticula  of  the  duodenum  in  contact  with  the 
head  of  the  pancreas  not  infrequently  occur,  and  doubt- 
less owe  their  origin  to  a  condition  resembling  that 
just  described.  Several  older  writers  quoted  by  Roth 
have  observed  such  diverticula,  and  Roth  has  described 
five  cases  in  which  the  mucosa  of  the  duodenum,  passing 
through  the  muscular  coat,  formed  a  hernial  protrusion 
into  the  head  of  the  pancreas.  In  two  of  these  cases 
two  diverticula  were  present ;  one  opened  beside  the 
bile  papilla  and  the  other  nearer  the  stomach  ;  in  one 
case  the  opening  of  the  last-named  pouch  was  in  con- 
tact with  the  papilla  of  the  duct  of  Santorini,  while  in 
the  other  its  relation  to  the  duct  was  not  noted.  In  a 
third  case  a  single  diverticulum  was  situated  beside  the 
smaller  papilla,  and  in  a  fourth  was  located  three  cen- 
timetres above  the  bile  duct,  but  its  relation  to  the 
smaller  papilla  was  not  observed.  In  a  fifth  case  the 
location  of  the  diverticulum  is  not  definitely  stated. 

The  following  case  illustrates  the  relationship  of 
diverticula  of  the  duodenum  to  the  pancreatic  and 
common  bile  ducts  : 

Specimen  XI. — Diverticula  of  the  duodenu??i  beside  the  bile  pa- 
pilla and  the  papilla  of  the  duct  of  Santorini.  In  the  mucous 
membrane  of  the  duodenum,  immediately  above  the  bile  papilla,  is 


ANOMALIES    OF   THE    PANCREAS.  65 

the  oval  orifice  of  a  diverticulum,  which  is  1.5  centimetres  in  length. 
After  partial  dissection  of  the  pancreas  from  the  duodenum,  the 
mucosa  is  found  to  form  a  hernial  protrusion  through  the  muscularis. 
This  diverticulum  penetrates  the  muscle  coat  beside  the  common  bile 
duct  as  the  latter  passes  obliquely  through  the  wall  of  the  intestine  and 
is  continued  upward  and  backward  in  the  direction  of  the  duct.  Im- 
mediately above  the  papilla  of  the  duct  of  Santorini  is  a  second 
somewhat  smaller  diverticulum,  1.3  centimetres  in  length,  provided 
with  an  oval  orifice.  It  passes  into  the  substance  of  the  pancreas 
above  the  duct,  and  consists  of  mucosa  and  submucosa,  in  contact 
with  which  are  lobules  of  pancreatic  tissue. 


One  of  the  diverticula  described  lies  beside  the 
common  bile  duct  as  it  penetrates  obliquely  the  duo- 
denal wall,  while  the  second  is  in  contact  with  the  duct 
of  Santorini.  Klebs,  Hansemann,  Fischer,  and  others 
have  shown  that  those  diverticula  of  the  mucosa,  which 
are  not  uncommon  near  the  mesenteric  attachment  of 
the  small  intestine,  occur  at  points  where  blood-vessels 
penetrate,  and  consequently  weaken  the  muscular 
coats.  Roth,  reviewing  the  cases  which  he  has  de- 
scribed, directs  attention  to  the  relative  frequency  with 
which  diverticula  of  the  duodenum  occur  in  contact 
with  the  pancreas,  and  quotes  the  conclusions  of 
Fleischmann  that  the  entrance  of  the  biliary  and  pan- 
creatic ducts  are  points  of  predilection,  because 
here  the  muscle  bundles  separate  to  allow  the  pas- 
sage of  the  ducts.  Pressure  within  the  intestine  pro- 
duces  a  protrusion  of  the  mucosa  through  the  muscu- 


66  DISEASE    OF   THE    PANCREAS. 

laris.  Such  a  diverticulum  is  analogous  to  that  which 
accompanies  an  accessory  pancreas,  and  doubtless  an 
additional  factor  in  their  production  is  the  previously 
described  occurrence  of  lobules  of  pancreatic  tissue 
separating  and  distorting  the  muscle  bundles  about  the 
ducts. 


CHAPTER    III. 

HISTOLOGY    OF    THE    PANCREAS THE    ISLANDS    OF 

LANGERHANS. 

Before  considering  the  pathological  histology  of 
chronic  interstitial  pancreatitis  and  the  alterations  of 
the  gland  associated  with  diabetes,  it  is  desirable  to 
discuss  in  detail  certain  histological  peculiarities  of  the 
gland.  The  pancreas  is  much  more  complex  in  struc- 
ture than  the  other  glandular  organs  which  it  closely 
resembles.  Langerhans,  in  an  inaugural  dissertation 
published  in  1869,  gave  the  first  careful  description  of 
its  histology,  and  showed  that  the  organ  has  not  the 
relatively  simple  structure  of  the  salivary  glands. 

Langerhans  studied  the  pancreas  of  rabbits,  which  in 
its  essential  features  does  not  differ  from  that  of  other 
mammals.  The  larger  ducts  are  lined  by  epithelium, 
composed  of  a  single  layer  of  high  columnar  cells.  As 
the  branches  of  the  ducts  become  smaller  the  epi- 
thelial cells  become  lower,  cubical,  and  finally  flat,  or, 
as  seen  in  section,  spindle-shaped,  the  nucleus  occu- 
pying the  thicker  central  part.  The  smallest  ducts 
end  in  the  acini,  composed  of  high  columnar  character- 
istically glandular  cells,  containing  next  the  lumen 
numerous  zymogen  granules.  Within  almost  every 
acinus,  in  contact  with  the  secreting  cells,  Langerhans 

67 


68  DISEASE    OF   THE    PANCREAS. 

found  one,  two,  or  more  cells  of  a  different  nature,  and 
to  these  he  gave  the  name  centro-acinar  cells.  They 
closely  resemble  the  flat,  spindle-shaped  cells  lining 
the  very  small  ducts,  and  he  thinks  that  the  epithelium 
of  the  duct  is  continued  over  the  secreting  cells  into 
the  lumen  of  the  acinus,  but  he  admits  that  he  is  unable 
to  determine  with  exactness  the  method  by  which  the 
duct  ends. 

Distributed  at  intervals  in  the  parenchyma  are  groups 
of  cells  differing  markedly  from  those  of  the  ordinary 
glandular  type.  Such  groups  are  usually  round,  and  in 
tissue  treated  for  two  or  three  days  with  Miiller's  fluid 
appear  with  low  magnification  as  intensely  yellow 
specks.  With  high  magnification  they  are  found  to  be 
composed  of  small,  irregularly  polygonal  cells,  with  a 
round  nucleus  and  refractive  homogeneous  cell-body. 
Of  the  nature  of  these  cell-groups  Langerhans  declares 
himself  entirely  ignorant. 

Numerous  observers  have  described  these  struc- 
tures, which  are  usually  designated  islands  of  Langer- 
hans. Renaut,  regarding  them  as  analogous  to  lymph 
follicles,  speaks  of  them  as  "points  folliculaires." 
Podwyssotski  calls  them  pseudo-follicles.  They  have 
been  designated  secondary'-  cell-groups,  interalveolar 
cell-islets,  and  interacinar  islands. 

In  injected  specimens  Kiihne  and  Lea  found  scattered 
throughout  the  organ  glomerular  structures  composed 
of  dilated   and   tortuous   capillaries,   and   showed   that 


HISTOLOGY   OF   THE    PANCREAS.  69 

they  correspond  to  the  cell-groups  which  Langerhans 
described.  The  interacinar  islands  are  penetrated  by 
numerous  wide,  tortuous  capillaries  forming  irregular 
anastomosing  columns.  Material  injected  into  the  duct 
of  the  gland  does  not  enter  the  island  of  Langerhans, 
and  Dogeil  was  able  to  demonstrate  by  Golgi's  stain  the 
absence  of  ducts  within  them. 

Numerous  investigations  have  demonstrated  the  oc- 
currence of  similar  structures  in  a  great  variety  of 
vertebrate  species,  including  numerous  mammals,  birds, 
amphibia,  reptiles,  and  fish.  Harris  and  Gow  studied 
these  bodies  in  a  large  number  of  mammals,  and  noted 
minor  differences  of  structure  in  different  species. 
Studies  of  the  Italian  observers,  Giannelli  and  Giaco- 
mini,  Massari,  and  Diamare,  have  dealt  with  the  re- 
lated bodies  of  lower  vertebrates.  Giannelli  and  Gia- 
comini  state  that  in  certain  reptiles  the  columns  of  cells 
forming  the  islands  of  Langerhans  have  a  tubular 
structure,  being  composed  of  moderately  high  cylindrical 
cells  which,  though  they  differ  in  appearance  from  the 
ordinary  secreting  cells  of  the  acini,  are  arranged  about 
a  narrow  lumen.  At  the  periphery  of  the  island  these 
tubular  columns  are  continuous  with  the  secreting 
acini.  In  certain  fish  Diamare  found  near  the  spleen 
the  hepatic  artery,  and  in  other  situations  isolated 
structures  havino-  the  characters  of  islands  of  Laneer- 
hans.  Since  islands  of  Langerhans  have  been  found 
in  a  constantly  increasing  number  of  diverse  species. 


70  DISEASE    OF   THE  PANCREAS. 

there  can  be  little  doubt  that  they  are  present  in  all 
vertebrates. 

The  Lobule  of  the  Pancreas. — In  order  to  determine 
the  relation  of  the  interacinar  islands  to  the  other  ele- 
ments of  the  gland  I  have  studied  the  human  pancreas 
under  a  great  variety  of  conditions.  The  organ  has 
been  studied  in  lower  animals,  particularly  in  cats  and 
dogs,  and  numerous  injections  of  the  blood-vessels  and 
of  the  ducts  have  been  made. 

In  the  human  pancreas  groups  of  acini  about  terminal 
ducts  are  not  sharply  defined  by  connective  tissue,  so 
that  individual  lobules,  as  in  the  human  liver,  are  indis- 
tinctly marked  off  and  in  places  apparently  fuse  with  one 
another.  In  the  pancreas  of  the  cat  the  lobules,  like 
those  in  the  liver  of  the  pig,  are  much  more  sharply 
outlined  by  interstitial  tissue.  The  parenchyma  is  di- 
vided by  septa  of  fibrous  tissue  into  small  polygonal 
areas  varying  in  size  and  shape.  When  injected  with 
Berlin  blue  a  small  ramification  of  the  duct  is  found  to 
penetrate  the  isolated  group  of  acini.  These  smallest 
subdivisions  of  the  parenchyma,  which  may  be  desig- 
nated primary  lobules,  often  appear  completely  isolated 
by  fibrous  tissue  from  those  near  by  ;  but  when  one  of 
them  is  traced  through  a  series  of  sections,  its  demar- 
cation being  incomplete,  one  may  find  the  parenchyma 
of  adjacent  lobules  continuous  in  places.  That  such 
polygonal  subdivisions  are  actually  independent  of  one 
another  and  represent  units  of  structure  is  readily  de- 


Fig.  9. — Supporting  connective-tissue  framework  of  a  pancreatic  lobule  after  digestion  of 
the  parenchyma  by  pancreatin.  From  a  specimen  prepared  by  the  method  of  Professor  J.  M. 
Flint. 


Fig.  io. — Chronic  interstitial  pancreatitis  in  the  cat,  following  ligation  of  the  pancreatic  ducts. 
The  lobules  are  defined  by  septa  oi  connective  tissue;  in  the  centre  of  almost  every  lobule  is 
an  island  of  Langerhans  From  a  photograph,  for  the  preparation  of  which  thanks  are  due  to 
Dr.  Charles  Potter. 


HISTOLOGY   OF   THE    PANCREAS. 


71 


monstrated  by  causing  an  inflammatory  increase  of  the 
interstitial  tissue.  If  the  pancreatic  ducts  of  a  cat  are 
ligated  and  the  animal  killed  at  the  end  of  two  or  three 
weeks,  the  gland  is  found  to  be  the  seat  of  chronic 
interstitial  inflammation,  characterized  by  an  increase 
of  the  interlobular  tissue  (see  Fig.  10).  The  lobules 
are  completely  separated  from  one  another  by  narrow 
bands  of  firm  fibrous  tissue  and  appear  in  sections  at 
rounded,  triangular,  or  polygonal  areas  of  parenchyma. 

The  islands  of  Langerhans  in  the  normal  pancreas 
of  the  cat  occupy  a  position  near  the  centre  of  the 
lobule,  and  in  the  splenic  end  of  the  gland  each  lobule 
contains  an  island.  In  a  given  section  many  lobules, 
of  which  the  limits  are  more  or  less  distinctly  outlined, 
are  seen  to  contain  islands  situated  near  their  centre, 
while  in  neighboring  lobules  such  structures  may  not 
be  discoverable.  If,  however,  serial  sections  (see  Fig. 
11)  are  studied,  every  lobule  is  found  to  contain  an 
island.  Its  presence  within  the  lobule  is  not  constant 
in  other  parts  of  the  organ,  and  at  the  extremity  of 
the  descending  arm  of  the  gland  islands  of  Langerhans 
are  very  few  in  number. 

The  framework  of  a  typical  pancreatic  lobule  is  well 
seen  in  the  accompanying  reproduction  of  a  photo- 
graph (see  Fig.  9)  kindly  given  me  by  Professor  Flint, 
of  the  University  of  California.  The  preparation  was 
made  by  digestion  according  to  the  method  which  he 
has  described.     An  island  of  Langerhans  marked  out 


72  DISEASE    OF   THE   PANCREAS. 

by  coarser  strands  of  stroma  is  situated  near  the  centre 
of  a  lobule.  A  somewhat  finer  net-work  contains  in  its 
meshes  the  secreting  acini. 


Fig.  II. — Camera  lucida  tracing  of  the  lobule  boundaries  in  one  of  a  series  of  sections  from 
the  splenic  end  of  a  cat's  pancreas.  The  majority  of  the  lobules  are  well  defined.  Those 
marked  d,  e,  f,  g,SinA  h  are  poorly  outlined,  but  are  found  to  be  more  readily  distinguishable 
■when  traced  through  the  series  of  sections.  The  lobules,  which  are  lettered  (a  to  o),  were  traced 
through  the  series,  and  each  was  found  to  contain  an  island  of  Langerhans  situated  near  its  centre. 
The  section  passes  through  the  island  in  lobules  a,  e,  i,j  and  n. 

Primary  lobules  of  the  cat's  pancreas  are  grouped 
about  the  medium-sized  ducts.  The  main  ducts  give  off 
branches  approximately  at  right  angles  to  their  course. 
Branching  one  or  more  times,  such  a  duct  forms  the 
centre  of  a  group  of  lobules,  which  is  usually  elongated 


HISTOLOGY    OF   THE    PANCREAS.  73 

in  form  and  tapers  to  a  point  at  or  near  the  surface  of 
the  g-land.  These  lobule-groups,  or  secondary  lobules, 
as  they  may  be  conveniently  called,  are  separated  from 
one  another  by  relatively  wide  bands  of  areolar  tissue, 
much  looser  in  texture  than  that  separating  the  indi- 
vidual lobules.  The  lobule-groups  in  the  fresh  state 
or  in  tissue  macerated  a  few  days  in  Mliller's  fluid  may 
be  separated  from  one  another  by  careful  teasing.  In 
the  loose  tissue  lie  the  larger  ducts,  arteries,  veins, 
and  nerves.  An  artery  and  vein  penetrate  each  lobule- 
group  in  company  with  the  duct  and  ramify  between 
its  lobules.  The  smallest  arteries  occasionally  pene- 
trate the  lobules,  but  usually  interlobular  branches 
diminishing  in  size  give  off  capillaries  which  enter  the 
lobule  and  form  a  close  net-work  between  the  glandu- 
lar acini. 

The  capillaries  of  the  island  of  Langerhans  form  a 
glomerulus  of  tortuous,  freely  anastomosing  vessels, 
much  wider  than  those  between  the  acini.  A  single 
afferent  vessel  like  that  of  the  glomerulus  of  the  kidney 
does  not  enter  this  group  of  dilated  capillaries,  but 
numerous  anastomoses  make  it  continuous  with  the  in- 
teracinar  capillaries.  When  Berlin  blue  is  injected 
through  the  aorta  into  the  arteries  of  the  pancreas  it 
not  infrequently  happens  that  in  parts  of  the  gland 
which  are  poorly  injected  the  vessels  of  the  island  are 
filled  with  the  injected  mass,  while  the  surrounding 
capillaries  are  for  the  most  part  empty.     If,  instead  of 


74 


DISEASE    OF   THE    PANCREAS. 


soluble  Berlin  blue,  a  granular  injection  mass,  for  ex- 
ample, cinnabar  or  ultramarine  blue,  is  used,  the  island 
may  be  injected  while  the  interacinar  capillaries  contain 
little  of  the  injected  material.  The  glomerular  net-work 
is  in  very  free  communication  with  the  smallest  arteries 
and  apparently  has  a  richer  blood  supply  than  other 
parts  of  the  lobule. 

In  the  human  pancreas  primary  lobules  and  lobule- 
groups  are  not  so  regularly  arranged  as  in  the  cat,  but 
both  structures  are  definable.  The  lobules  vary  much 
in  size  and  are  usually  not  clearly  separated  from  one 
another.  Though  an  island  of  Langerhans  is  often  situ- 
ated in  the  centre  of  a  more  or  less  clearly  defined 
lobule,  no  constancy  of  position  is  discoverable.  The 
lobule-groups,  or  secondary  lobules,  are  separated  by 
relatively  wide  bands  of  loose  areolar  tissue  in  which 
are  contained  the  medium-sized  ducts,  the  blood-vessels, 
and  the  nerves.  Within  the  secondary  lobule  the  arte- 
ries and  veins,  which  are  side  by  side,  do  not,  as  in  the 
cat,  accompany  the  ducts.  As  pointed  out  in  a  previous 
chapter,  several  secondary  lobules  are  usually  grouped 
together  to  form  tertiary  lobules,  and  these  represent 
the  largest  subdivisions  seen  upon  the  surface  of 
the  organ. 

Morphology  of  the  Islands  of  Langerhans. — Various 
opinions  have  been  held  concerning  the  nature  of  the 
interacinar  cell-groups,  and  a  number  of  observers,  de- 
nying the  epithelial  character  of  the  cells  which  com- 


HISTOLOGY    OF   THE    PANCREAS.  75 

pose  them,  have  emphasized  a  supposed  resemblance  to 
lymphoid  tissue.  By  certain  methods  of  preparation, 
notably  after  hardening  in  alcohol,  the  cell  protoplasm 
is  inconspicuous,  and  the  nucleus  deeply  stained  may 
resemble  that  of  a  lymphocyte  ;  the  arrangement  of 
cells  in  groups  within  the  meshes  of  a  capillary  net-work 
gives  superficially  the  appearance  of  a  lymphoid  follicle. 

Renaut  has  described  the  pancreas  as  a  lympho- 
glandular  organ  composed,  he  has  conceived,  of  glan- 
dular structures  and  lymphoid  tissue  in  intimate  relation. 
He  has  described  the  cell-groups  as  "points  foUiculaires" 
in  which  cells  of  a  glandular  type  are  situated  in  the 
meshes  of  a  reticular  tissue.  Mouret  has  supported 
Renaut's  somewhat  ill-defined  conception  of  a  lympho- 
glandular  organ,  but  has  regarded  the  cell-groups  as 
small  masses  of  lymphoid  tissue.  Kiihne  and  Lea 
and  Dieckhoff  think  it  probable  that  they  are  small 
lymph  follicles.  Schlesinger  regards  them  as  a  variety 
of  lymph  follicle  of  which  the  cells  differ  from  those 
of  ordinary  lymphoid  tissue.  Podwyssotski  calls  them 
pseudo-follicles,  and  states  that  though  they  resemble 
lymph  follicles  their  cells  have  nothing  in  common  with 
lymphoid  cells  ;  while  Renaut  in  his  recent  treatise  on 
histology,  abandoning  his  former  view,  describes  the 
common  origin  of  the  interacinar  cell-groups  and  the 
secreting  acini. 

It  has  been  suggested  by  several  observers,  Laguesse 
and  others,  that  the  islands  of  Langerhans  represent  a 


76  DISEASE   OF  THE   PANCREAS. 

stage  in  the  embryologlcal  development  of  the  glandular 
acini,  those  found  in  the  adult  organ  being  persistent 
rudimentary  structures.  Subsequent  observations  upon 
the  histogenesis  of  the  pancreas  have  caused  Laguesse 
to  abandon  this  view. 

When  throughout  the  pancreas  are  found  structures 
composed  of  cells  differing  from  those  of  the  acini, 
having  a  different  arrangement  and  bearing  a  peculiar 
relation  to  the  blood-vessels,  it  seems  probable  that, 
formed  in  embryologlcal  life,  they  possess  an  anatomical 
identity  as  definite  as  that  of  the  glomeruli  of  the  kid- 
neys or  of  the  Malpighian  bodies  of  the  spleen,  and  like 
them  subserve  some  special  function.  Schaffer  directs 
attention  to  their  similarity  to  the  small  ductless  struc- 
tures, the  carotid  and  coccygeal  glands  and  the  para- 
thyroid bodies,  which  are  also  composed  of  anasto- 
mosing columns  of  epithelial  cells. 

The  epithelial  nature  of  the  cells  composing  the 
islands  of  Langerhans  has  been  clearly  demonstrated 
by  embryologlcal  investigation.  Laguesse  has  studied 
the  development  of  these  bodies  in  the  embryo  sheep. 
He  finds  that  at  an  early  period  of  growth  the  pancreas 
is  composed  of  tortuous  anastomosing  tubules  formed 
by  a  single  layer  of  epithelial  cells.  Here  and  there 
occur  cells  which  stain  more  deeply  than  those  about 
them  and,  like  the  border  cells  of  the  stomach,  are  situ- 
ated near  the  outer  surface  of  the  tubule.  These  cells 
proliferate  to  form  solid  outgrowths  upon  the  tubule  and 


HISTOLOGY    OF    THE    PANCREAS.  ^'^ 

constitute  what  he  calls  primary  islands  of  Langerhans. 
At  a  later  stage  the  secreting  acini  are  formed  as  buds, 
from  the  wall  of  the  original  tubules,  and  within  them  can 
be  recognized  two  kinds  of  cells,  the  ordinary  glandular 
cell  containing  zymogen  granules  and  the  centro-acinar 
cells  which  form  a  second  more  or  less  continuous  row 
superimposed  upon  the  secreting  cells.  At  a  still  later 
stage  islands  of  Langerhans  continue  to  be  formed,  but 
their  development  differs  from  that  of  those  which  are 
first  formed,  for,  accepting  the  observations  of  Lewas- 
chew  to  be  mentioned  later,  Laguesse  thinks  that  groups 
of  acini  undergo  alterations  by  which  they  are  trans- 
formed into  interacinar  islands,  designated  by  him 
secondary  islands  of  Langerhans.  This  mode  of  forma- 
tion has  not  been  confirmed,  and,  as  will  be  shown  later, 
does  not  occur. 

Renaut  has  described  the  histogenesis  of  the  pan- 
creatic lobule.  His  description  of  the  early  stages  of 
development  agrees  with  that  given  by  Laguesse. 
The  primitive  dorsal  and  ventral  outgrowths  from  the 
wall  of  the  duodenum  form  numerous  branches  which 
ramify  in  the  dorsal  mesentery  of  the  intestine.  At 
first  these  branches  are  solid,  but  soon  they  acquire  a 
lumen  about  which  the  cells  are  arranged  in  a  single  row, 
and,  anastomosing  between  themselves,  they  resemble 
the  tubular  columns  which  form  the  liver  of  certain 
lower  vertebrates.  At  intervals  along-  their  walls  are 
formed  short  outgrowths   terminating  in  a  rosette-like 


78  DISEASE    OF   THE   PANCREAS. 

group  of  blind  pouches.  At  the  base  or  within  such  a 
group  of  primitive  acini  at  least  one  island  of  Langer- 
hans  is  formed  by  differentiation  and  multiplication  of 
the  peculiar  cells  already  described  by  Laguesse.  The  - 
rosette-like  group  of  acini  and  at  least  one  island  of 
Langerhans  represent  the  primary  gland  lobule  in  its 
undev.eloped  form,  and  by  subsequent  growth  give  rise 
to  the  primary  lobule  of  the  adult  gland. 

The  cells  which  compose  the  interacinar  islands  in 
the  adult  human  pancreas  resemble  in  type  the  epithe- 
lial cells  of  the  acini.  They  have  a  large,  round,  occa- 
sionally oval  vesicular  nucleus  and  well-defined  cell- 
body.  The  basal  zone  of  the  secreting  cell,  as  is  well 
known,  stains  deeply  with  nuclear  dyes,  for  example, 
hsematoxylin  or  methylene  blue,  while  the  central 
part,  which  contains  zymogen  granules,  remains  un- 
stained. The  cells  of  the  island,  on  the  contrary,  are 
by  nuclear  dyes  entirely  unstained,  while  with  eosin  their 
protoplasm  takes  a  homogeneous  bright  pink  color. 
The  nuclei  differ  but  little  from  those  of  neighboring 
acini ;  they  vary  considerably  in  size,  and  not  infre- 
quently one  finds  very  large,  round  vesicular  nuclei 
the  diameter  of  which  is  two  or  more  times  that  of  the 
adjacent  cells.  Occasionally  the  cells,  forming  columns 
between  which  lie  anastomosing  capillaries,  are  very 
closely  packed  together,  and  nuclei  are  situated  almost 
side  by  side  ;  more  frequently  the  cells  of  the  island  are 
less  numerous  and  nuclei  are  less  closely  crowded. 


HISTOLOGY   OF   THE   PANCREAS.  79 

Dog-iel  and  later  Stangl  have  shown  that  fat  is 
normally  present  in  the  protoplasm  of  the  cells.  Nu- 
merous very  fine  droplets  of  almost  uniform  size  are 
abundant  in  the  islands  of  Langerhans,  while  fat  drop- 
lets within  the  secreting  acini,  often  much  larger,  vary 
greatly  in  size  and  are  more  sparsely  scattered. 

The  outline  of  the  island  is  usually  round  or  oval, 
and  is  not  infrequently  accentuated  by  a  delicate  circle 
of  fibrous  tissue.  In  other  instances  the  outline  is  less 
sharp  and  the  body  accommodates  its  shape  to  that 
of  the  neighboring  acini.  Occasionally  one  sees,  ap- 
parently within  the  island,  cells  arranged,  as  in  the 
acini,  about  a  central  lumen,  and  indeed  in  many  in- 
stances it  is  difficult  to  convince  one's  self  that  they  do 
not  form  part  of  it.  An  impression  is  produced  that 
the  columns  of  the  island  are  in  continuity  with  cells 
having  an  acinar  arrangement.  Since  the  islands  and 
the  secreting  acini  have  a  common  origin,  it  is  not 
inconceivable  that  they  may  occasionally  remain  con- 
tinuous in  the  adult  organ.  When  the  foetal  pancreas 
is  affected  by  congenital  syphilis,  the  islands  of  Langer- 
hans, I  have  found,  retain  their  continuity  with  the 
secreting  structures  (see  chapter  vii.). 

In  the  human  pancreas  islands  of  Langerhans  were 
found  to  be  more  numerous  in  the  splenic  end  or  tail 
than  elsewhere.  To  obtain  a  numerical  statement  of 
their  relative  abundance,  their  number  was  determined 
n  a  sectional  area  of  0.5  square  centimetre.      Sections 


8o 


DISEASE    OF   THE    PANCREAS. 


about  ten  micromillimetres  thick  were  made  (a)  from  the 
enlarged  duodenal  part  of  the  pancreas, — that  is,  from  the 
head, — (d)  from  the  mid-part  of  the  body,  and  (c)  from 
the  splenic  end  or  tail.  The  following  table  gives  the 
number  in  0.5  square  centimetre  of  sections  taken  from 
the  head,  body,  and  tail  of  ten  normal  organs  : 

TABLE. 


Number. 

Head. 

Body. 

Tail. 

I 

1 1 

13 

25 

30 

42 

2 ... 

30 

3 

4 

4 

19 

4 .    .    ,    . 

4 

10 

13 

5 

27 

18 

59 

6 

25 

27 

26 

7 

18 

18 

29 

8 

6 

10 

29 

9 - 

44 

32 

61 

10 

14 

23 

32 

Mean 

18.3 

18.0 

34-0 

The  table  shows  that  islands  of  Langerhans  are 
more  abundant  in  the  tail  or  splenic  end  than  in  the 
head  or  in  the  body,  where  they  are  present  in  ap- 
proximately equal  number.  They  are  almost  twice  as 
numerous  in  sections  from  the  tail  as  in  those  from 
other  parts  ;  but  since  the  number  in  only  one  plane  is 
recorded,  in  order  to  obtain  their  actual  relative  abun- 
dance it  is  necessary  to  square  these  figures  They  are 
then  found  to  be  slightly  less  than  three  and  a  half 
times  as  numerous  in  the  tail  as  elsewhere. 

The  islands  of  Langerhans  are  more  numerous,  as 
pointed  out  by  Kasahara,   in   the  pancreatic  tissue  of 


HISTOLOGY   OF   THE    PANCREAS.  8 1 

the  foetus  and  of  very  young  children  than  in  the 
adult.  Should  we  assume  that  they  are  formed  during 
embr}^ological  development  and  persist  thereafter,  this 
fact  is  readily  explicable.  The  organ  being  much 
smaller  in  the  foetus  and  in  a  young  child,  the  same 
number  of  islands,  though  themselves  smaller,  are 
more  closely  together,  and  therefore  appear  to  be 
more  numerous  in  sections. 

Physiology  of  the  Islands  of  Langerhans. — An  attempt 
to  investigate  experimentally  the  nature  of  the  islands 
of  Langerhans  has  been  made  by  Lewaschew,  working 
in  Heidenhain's  laboratory.  He  studied  the  pancreas 
of  dogs  and  cats  killed  after  having  been  subjected  to 
conditions  which  cause  the  gland  to  secrete  actively. 
After  prolonged  overfeeding,  or  after  the  administra- 
tion of  pilocarpin,  which  stimulates  the  pancreas  as  it 
does  the  salivary  glands,  he  claims  to  have  found  struc- 
tures representing  transitions  between  the  glandular 
acini  and  the  interacinar  cell-groups.  He  has  observed 
acini  containing  one  or  more  cells  of  which  the  proto- 
plasm is  non-granular  and  stains  lightly.  A  whole 
acinus  or  a  number  of  acini  may  be  composed  of  these 
cells.  In  such  areas  some  of  the  cells  may  assume  a 
polygonal  shape  and  are  no  longer  grouped  about  a 
central  lumen.  Other  cell-groups  consist  entirely  of 
polygonal  cells  without  acinar  arrangement,  and  these 
represent,  he  thinks,  the  fully  formed  islands  of  Lan- 
gerhans. 


J 

82  DISEASE    OF   THE    PANCREAS. 

In  order  to  obtain  a  large  increase  in  the  number 
of  altered  acini  one  even  maximal  stimulation  of  the 
gland  is  not  sufficient ;  but  by  the  repeated  administra- 
tion of  pilocarpin  this  result  is  accomplished,  and  the 
longer  and  more  intense  the  action  of  the  drug  the 
greater  their  number.  To  cause  their  increase  by 
overfeeding,  a  very  large  quantity  of  food  is  necessary. 
Lewaschew  believes  that  the  cells  composing  the  inter- 
acinar  groups  may  reassume  their  character  of  secreting 
cells  and  again  form  acini.  He  mentions  that  he  has 
found  an  unusual  number  of  islands  under  conditions 
other  than  those  of  increased  functional  activity.  They 
were  very  numerous  in  a  dog  which  several  days  before 
its  death  had  suffered  with  fever. 

The  observations  of  Lewaschew  have  not  been  con- 
firmed. Statkewitsch  has,  however,  described  similar 
alterations  in  the  pancreas  of  dogs,  cats,  and  rabbits 
subjected  to  conditions  having  no  resemblance  to  those 
which  Lewaschew  produced.  In  animals  which  have 
been  starved,  the  secretino-  cells,  he  claims,  lose  their 
granular  inner  zone  and  by  a  series  of  transitions 
similar  to  those  described  by  Lewaschew  assume  the 
character  and  arrangement  of  the  interacinar  cell- 
groups.  He  thinks  that  his  researches,  as  well  as 
those  of  Lewaschew,  show  that  these  structures  are 
merely  the  result  of  an  intense  alteration  of  the  gland 
cells.  Jarotzky  has  made  a  careful  study  of  the  secreting 
pancreatic   cells   in   mice    under  various   conditions   of 


HISTOLOGY   OF   THE     PANCREAS.  83 

inanition  ;  from  some  of  his  animals  food  was  withheld, 
others  were  given  only  sugar,  others  only  fat,  but  in 
none  did  he  find  changes  similar  to  those  described  by 
Statkewitsch  ;  and  he  reaches  the  conclusion  that  the 
islands  of  Langerhans  are  independent  structures  em- 
bedded in  the  glandular  parenchyma. 

In  the  normal  human  pancreas  one  occasionally  finds 
groups  of  acini  composed  of  cells  differing  from  the 
typical  glandular  type  and  suggesting  a  transition  from 
the  secreting  cell  to  that  of  the  island  of  Langerhans. 
The  cell-protoplasm  does  not  take  the  nuclear  dye  as 
does  the  basal  part  of  the  ordinary  glandular  cell, 
and  when  stained  with  eosin  has  a  bright  pink  color 
and  homogeneous  refractive  appearance.  The  nucleus, 
which  shows  no  evidence  of  degenerative  change,  is 
situated  near  the  centre  of  the  cell.  Occasionally  one 
or  more  cells  of  the  character  described  form  part  of 
an  acinus  which  otherwise  resembles  those  about  it. 
Usually,  however,  a  group  of  acini  are  changed,  and 
such  an  area  often  corresponds  in  size  to  an  island  of 
Langrerhans. 

The  presence  of  such  groups  of  altered  acini  the 
cells  of  which  resemble  those  of  the  island  of  Langer- 
hans confirms  at  first  sight  the  view  of  Lewaschew, — 
namely,  that  groups  of  acini  may  assume  the  character 
of  the  interacinar  structures.  It  is  probable  that  these 
foci,  in  part  at  least,  represent  what  Laguesse  and 
Pischinger  have  described  as  stages  of  transition.     The 


84  DISEASE    OF   THE    PANCREAS. 

arrangement  of  more  or  less  columnar  cells  about  a 
central  lumen  is,  however,  still  preserved,  and  one  does 
not  find  similar  areas  in  which  this  arrangement  is  lost. 
The  lumen,  indeed,  is  usually  very  conspicuous  and  is 
often  considerably  dilated,  filled  with  products  of  secre- 
tion which  stains  deeply  with  eosin.  It  seems  probable 
that  these  groups  of  acini  are  altered  as  the  result  of 
peculiar  functional  activity,  it  may  be,  of  hyperstimula- 
tion  of  the  gland.  There  is  at  least  no  evidence  that 
they  represent  transitional  stages  between  glandular 
acini  and  islands  of  Langerhans. 

Such  altered  acini  are  observed  in  a  small  proportion 
of  normal  glands.  They  were  found  in  three  of  twenty- 
seven  glands  examined  carefully  for  their  presence. 
They  were,  moreover,  present  in  three  of  seven  relatively 
normal  organs  from  diabetic  patients.  The  occurrence  of 
voracious  appetite  and  increased  food  ingestion  in  indi- 
viduals so  affected  may  explain  the  occurrence  of  these 
areas  which  represent  possibly  foci  of  peculiar  secretory 
activity.  They  were  particularly  abundant  in  one  in- 
stance of  chronic  interstitial  pancreatitis  not  associated 
with  diabetes. 

I  have  attempted  to  confirm  the  observations  of  Lew- 
aschew  by  injecting  subcutaneously  pilocarpin  muriate 
into  doofs.  Since  the  number  of  islands  varies  in  dif- 
ferent  parts  of  the  gland,  it  was  considered  desirable 
to  study  sections  from  corresponding  parts  of  the 
organ.     Specimens  were  prepared  {a)  from  the  splenic 


HISTOLOGY   OF   THE   PANCREAS. 


85 


extremity,  {b)  from  the  part  which  is  in  contact  with  the 
duodenum,  and  [c]  from  the  descending  arm  which  lies 
in  the  mesentery  of  the  duodenum.  In  order  to  deter- 
mine with  accuracy  the  relative  abundance  of  the  islands, 
their  number  was  counted  in  a  measured  sectional  area 
and  compared  with  that  found  in  the  pancreas  of  an 
animal  to  which  pilocarpin  had  not  been  given. 

Following  is  a  summary  of  the  experiments  per- 
formed : 

Dog  No.  i. — The  animal  was  given  daily  for  nine  successive  days 
0.02  to  0.03  gramme  of  pilocarpin  muriate.  Profuse  salivation  was 
produced,  often  accompanied  by  vomiting  and  diarrhoea. 

Dog  No.  2. — During  twenty -eight  hours  pilocarpin  muriate  0.005 
to  0.0 1  gramme  was  injected  subcutaneously  six  times.  The  drug 
produced  repeatedly  profuse  flow  of  saliva. 

Dog  No.  3. — During  twenty-four  hours  pilocarpin  muriate  o.oi 
gramme  was  injected  subcutaneously  seven  times.  Profuse  salivation 
followed  each  injection. 

In  the  table  the  figures  represent  the  number  of 
islands  in  0.5  square  centimetre  of  sectional  area.  The 
letters  refer  to  the  parts  of  the  gland  indicated  above. 


Injected  Animal. 

Dog  No.  I  .    .    . 

Dog  No.  2  .    .    . 
Dog  No.  3  .    .    . 

Average   .... 


61 

55 
54 


56.6 


21 
20 

72 


37-6 


6.6 


Control   Animal. 

Dog  No.  I.  .  . 
Dog  No.  II.  .  . 
Dog  No.  III.  . 

Average  .... 


59 
39 
67 


55 


61 


67.6 


14 

3 

12 


9.6 


S6  DISEASE    OF   THE   PANCREAS. 

The  figures  show  that  no  increase  of  the  number  of 
islands  was  obtained  in  the  three  experiments.  Transi- 
tional stages  between  glandular  acini  and  interacinar 
islets  were  not  observed.  The  number  of  islands  in 
that  part  of  the  descending  arm  of  the  pancreas  which 
lies  in  the  mesentery  of  the  duodenum  (c)  is  constantly 
much  less  than  elsewhere ;  the  number  in  different 
glands  and  in  different  parts  of  the  same  gland  varies 
considerably.  In  the  experiments  of  Lewaschew  these 
sources  of  error  have  apparently  not  been  given  suffi- 
cient weight. 

The  diversity  of  the  opinions  concerning  the  struc- 
tures under  consideration  has  justified,  I  believe,  the 
preceding  detailed  discussion  of  their  nature.  Certain 
facts  may  be  considered  to  be  established.  The  islands 
of  L-angerhans  are  composed  of  cells  of  epithelial  type 
having  the  same  origin  as  those  which  form  the  acini. 
Ramifications  of  the  pancreatic  duct  do  not  penetrate 
the  interacinar  islands,  while  on  the  other  hand  these 
bodies  have  an  intimate  relation  to  the  vascular  system. 
They  occupy  a  definite  position  within  the  pancreatic 
lobule  (of  the  cat)  and  are  more  numerous  in  certain 
parts  of  the  gland  than  in  others.  It  is  not  possible  to 
transform  secreting  acini  into  islands  of  Langerhans. 

The  function  of  these  structures  has  been  the  subject 
of  some  speculation.  Harris  and  Gow,  and  more  re- 
cently Jarotzky,  have  suggested  that  they  are  concerned 
in  the  elaboration  of  the  pancreatic  secretion  furnishing 


HISTOLOGY   OF   THE    PANCREAS.  87 

possibly  one  or  other  ferment  which  it  contains.  Gian- 
nelli  and  Giacomini,  who  found  that  in  certain  reptiles 
the  cells  of  the  interacinar  islands  are  arrang^ed  about  a 
central  lumen,  hold  a  similar  view.  In  higher  animals, 
however,  numerous  observations  have  shown  that  the 
ducts  do  not  penetrate  the  interacinar  islands,  and  the 
staining  method  of  Golgi  employed  by  Dogiel  has  failed 
to  demonstrate  the  presence  of  ducts,  though  their  finest 
ramifications  become  apparent  in  the  adjacent  acini. 

The  intimate  relation  of  columns,  of  epithelial  cells  to 
a  rich  capillary  net-work  has  suggested  that  the  islands 
of  Langerhans  furnish  some  substance  to  the  blood, 
the  hypothetical  internal  secretion  of  the  pancreas. 
Abundant  experimental  research  inaugurated  by  von 
Mering  and  Minkowski  having  shown  that  the  pancreas 
exerts  an  important  influence  on  carbohydrate  metabo- 
Hsm,  several  writers,  Laguesse,  Schafer,  Diamare,  and 
others,  have  suggested  that  the  islands  of  Langerhans 
perform  this  function.  Ssobolew  claims  to  have  ob- 
tained experimental  evidence  that  assimilation  of  sugar 
causes  changes  in  the  cells  of  these  bodies  comparable, 
to  those  which  occur,  as  Heidenhain  has  shown,  in  the 
secreting  cells  as  the  result  of  increased  functional 
activity.  The  cells  of  the  interacinar  islands  are,  he 
states,  most  granular  after  hunger  which  has  lasted  two 
or  three  days,  but  after  feeding  with  carbohydrates  in 
considerable  quantity,  or  after  intravenous  injection  of 
sugar,   the  granules  within  the  cells  diminish  in  num- 


88  DISEASE    OF   THE   PANCREAS. 

ber.  Schmidt,  however,  was  unable  to  produce  similar 
phenomena  in  mice  and  in  guinea  pigs  after  intraperi- 
toneal and  intravenous  injection  of  solutions  of  sugar. 

The  study  of  pathological  changes  associated  with  the 
disease  of  carbohydrate  metabolism,  diabetes  mellitus, 
has  afforded  convincing  evidence  that  the  islands  of 
Langerhans  control  the  assimilation  of  sugar.  It  will 
be  the  purpose  of  a  subsequent  chapter  to  define  the 
relationship  of  diabetes  mellitus  to  diseases  of  the  pan- 
creas and  to  alterations  of  the  islands  of  Langerhans. 


CHAPTER    IV. 

VARIETIES    OF    ACUTE    PANCREATITIS. 

Acute  inflammation  of  the  pancreas  has  attracted 
much  attention,  yet  the  nature  and  the  cause  of  the 
lesions  which  accompany  it  have  been  involved  in  ob- 
scurity. While  diffuse  suppurative  inflammation  or 
more  localized  abscess  formation  resembles  similar 
processes  frequently  observed  in  other  organs,  so- 
called  hemorrhagic  and  gangrenous  pancreatitis  finds 
little  analogy  in  the  liver,  spleen,  kidneys,  or  indeed  in 
the  salivary  glands,  which  resemble  in  many  respects 
the  pancreas.  The  difficulty  of  deciding  what  shall  be 
regarded  an  inflammatory  process  is  here  encountered  ; 
distinctions  between  hemorrhagic  pancreatitis  and  hem- 
orrhage into  the  organ,  though  usually  emphasized  in 
writings  upon  diseases  of  the  gland,  are  not  clearly 
drawn. 

A  well-defined  classification  of  acute  lesions  of  the 
gland  was  introduced  by  Fitz,  and  was  based  upon  an 
analysis  of  cases  studied  by  himself,  as  well  as  of  those 
recorded  in  the  literature.  Inflammatory  changes  asso- 
ciated with  hemorrhage  into  the  organ,  so-called  hem- 
orrhagic pancreatitis,  had  already  been  observed  by 
Rokitansky  and  by  Klebs. 

Both  Friedreich  and  Fitz  recognized  as  an  indepen- 


90  DISEASE   OF   THE   PANCREAS. 

dent  condition,  pancreatic  hemorrhage,  a  lesion  un- 
accompanied by  inflammatory  changes.  The  existence 
of  acute  inflammation,  according  to  Fitz,  is  estabHshed 
from  an  anatomical  stand-point  by  the  occurrence  of 
degenerative  changes  in  the  parenchymatous  cells  and 
by  exudation  into  the  interstitial  tissue  ;  but  even  when 
anatomical  evidence  is  lacking,  clinical  symptoms  may 
demonstrate  the  presence  of  an  inflammatory  process  ; 
the  uncertain  evidence  of  fever  and  other  symptoms 
of  inflammation  may  suggest  hemorrhagic  pancreatitis 
rather  than  simple  hemorrhage.  Fitz  found  that  acute 
inflammatory  alterations  of  the  pancreas  fell  into  three 
groups  which,  to  emphasize  their  conspicuous  feature, 
he  designated  hemorrhagic,  suppurative,  and  gangre- 
nous pancreatitis. 

Hemorrhagic  pancreatitis,  described  by  Fitz,  occurs 
most  frequently  in  those  who  have  had  previous  attacks 
of  "gastric  or  gastro-duodenal  dyspepsia."  It  begins 
with  intense  pain  in  the  upper  abdomen,  followed  by 
vomiting  and  not  infrequently  by  slight  swelling  of  the 
epigastrium,  associated  with  tenderness  and  accompa- 
nied by  obstinate  constipation.  The  temperature  is 
normal  or  subnormal,  and  symptoms  of  collapse  precede 
death,  which  usually  occurs  between  the  second  and 
fourth  days.  The  pancreas  is  found  to  be  enlarged, 
and  its  interstitial  tissue,  as  well  as  the  tissues  in  its 
neighborhood,  is  infiltrated  with  blood.  Microscopic 
examination  shows  the  presence  of  cellular  and  fibrin- 


VARIETIES    OF   ACUTE    PANCREATITIS. 


91 


ous  exudates  together  with  necrosis  of  the  paren- 
chyma. In  the  fat  of  the  omentum  and  of  the  sub- 
peritoneal tissue  are  the  disseminated  foci  of  necrosis 
to  which  Balser  has  directed  attention. 

Suppurative  pancreatitis  resembles  suppurative  in- 
flammation of  other  organs  ;  the  gland  may  contain  ab- 
scess cavities  of  varying  size,  the  organ  being  enlarged 
and  the  peri-pancreatic  tissue  indurated.  Suppurative 
inflammation  rarely  pursues  an  acute  course,  but  per- 
sists for  weeks  or  months,  and  abscess  cavities  may 
discharge  into  the  stomach  or  duodenum,  or,  rupturing 
into  the  lesser  peritoneal  cavity,  may  here  produce  an 
abscess  cavity  of  great  size.  Pylephlebitis  and  abscess 
of  the  liver  may  accompany  this  condition. 

Gangrenous  pancreatitis,  according  to  Fitz,  though 
it  may  follow  other  conditions,  is  usually  the  result  of 
hemorrhagic  pancreatitis,  and  in  at  least  half  of  the 
recorded  cases  evidence  of  previous  hemorrhage  has 
been  present  in  the  altered  gland.  The  clinical  symptoms 
of  the  two  conditions  resemble  one  another  closely,  but 
where  the  pancreas  is  found  to  be  gangrenous  the 
illness  has  been  of  longer  duration,  proving  fatal  at  the 
end  of  several  weeks.  The  organ  is  enlarged,  often 
soft  and  friable,  and  of  a  color  which  varies  from  mottled 
red  and  gray  to  dark  brown  or  black  ;  by  extension 
of  the  gangrenous  process  to  the  tissues  about  the  organ 
almost  complete  sequestration  may  result.  Since  the 
gangrenous    pancreas     lies    in    the    posterior    wall    of 


92 


DISEASE   OF   THE    PANCREAS. 


the  lesser  peritoneal  cavity,  peritonitis  ensues,  and 
this  cavity  is  converted  into  an  abscess  containing 
pus  and  necrotic  material.  In  some  cases  the  com- 
pletely sequestrated  pancreas,  attached  by  only  a 
few  shreds  of  tissue,  is  surrounded  by  purulent 
fluid.  Communication  may  be  formed  with  the  in- 
testine, and  in  two  cases  described  by  Chiari  a  large 
mass  of  necrotic  material  discharged  by  the  rectum 
was  recognized  to  be  gangrenous  pancreatic  tissue. 
Disseminated  fat  necrosis,  to  be  described  later,  ac- 
companies the  lesion. 

Suppurative  inflammation  of  the  pancreas  does  not 
differ  essentially  from  that  of  other  organs,  and  pre- 
sents no  noteworthy  peculiarities.  Fitz  has  pointed 
out  that  disseminated  fat  necrosis  is  uncommon  with 
this  condition,  though  almost  constantly  found  in  asso- 
ciation with  hemorrhagic  and  gangrenous  inflammation. 

Pancreatic  Hemorrhage — Of  especial  interest  is  the 
occurrence  of  hemorrhage,  often  fatal,  into  and  about 
the  pancreas,  the  so-called  pancreatic  apoplexy,  com- 
parable, it  has  been  thought,  to  cerebral  apoplexy. 
Hemorrhage  occurring  into  the  substance  of  the  gland 
may  be  caused  by  a  variety  of  factors  which  present 
nothing  peculiar  to  the  organ,  and  are  familiar  in  other 
tissues  of  the  body.  Vessels  may  be  ruptured  by 
traumatism,  and  here,  as  elsewhere,  hemorrhage  may 
accompany  the  presence  of  tumors  ;  the  contents  of 
pancreatic  cysts  are  not  infrequently  bloody.     Hemor- 


VARIETIES   OF   ACUTE    PANCREATITIS.  93 

rhage  of  such  character,  as  well  as  the  minute  hem- 
orrhages observed  In  association  with  purpura,  eclamp- 
sia, and  acute  infectious  diseases  are  dependent  upon 
factors  which  determine  their  occurrence  in  other 
organs  and  have  little  in  common  with  the  peculiar 
hemorrhagic  lesion  to  which  the  pancreas  is  subject. 

Hemorrhage  into  the  pancreas  occurring  in  an  indi- 
vidual previously  supposed  to  be  in  good  health  may- 
be the  only  lesion  found  to  explain  the  fatal  termination 
of  an  illness  lasting  only  a  few  hours.  The  literature 
of  pancreatic  affections  contains  numerous  examples  of 
so-called  pancreatic  apoplexy  of  which  the  sudden  onset 
and  rapidly  fatal  end  suggest  an  analogy  with  the  more 
frequent  cerebral  hemorrhage.  The  quantity  of  blood 
escaping  from  the  vessels  does  not  bear  a  direct  relation 
to  the  severity  of  the  lesion.  Such  a  condition  was 
described  by  Spiers,  in  1866,  and  since  other  writers, 
notably  Zenker,  Prince,  Draper,  and  Seitz,  have  recorded 
additional  instances. 

In  some  cases  cited  as  examples  of  pancreatic  hemor- 
rhage it  is  improbable,  as  Seitz  points  out,  that  the 
pancreatic  lesion  was  in  reality  the  cause  of  death,  and 
in  the  cases  described  by  Reubold  and  Rehm,  after 
death  from  poisoning  with  morphia,  after  strangling,  or 
after  hemorrhage  from  the  femoral  vein,  the  interstitial 
tissue  of  the  gland  and  its  immediate  vicinity  has  been 
the  seat  of  such  moderate  hemorrhamc  infiltration  that 
extravasation  of  blood  may  have  been  the  result  of  post- 


94  DISEASE   OF   THE   PANCREAS. 

mortem  self-digestion.  There  remains,  however,  a  large 
number  of  cases  where,  following  sudden  death,  a  care- 
ful autopsy  has  disclosed  no  noteworthy  disease  other 
than  an  extensive  hemorrhagic  lesion  of  the  pancreas. 

Klebs  thought  that  hemorrhage  occurring  in  the 
absence  of  inflammatory  changes  might  be  due  to  cor- 
rosive action  of  the  pancreatic  juice  upon  the  blood- 
vessels. Fitz  recalls  the  fact  that  fluids  injected  into 
the  arteries  of  a  dead  body  are  prone  to  escape  in  the 
neighborhood  of  the  pancreas,  and  suggests  that  where 
arterial  sclerosis  exists  hemorrhage  occurs  because 
the  arteries  of  the  pancreas  are  peculiarly  susceptible 
to  rupture ;  he  adds,  however,  that  in  the  great  majority 
of  cases  there  is  no  evidence  of  arterial  disease.  It  has 
been  maintained  by  Seitz  that  in  a  limited  number  of 
cases  arterial  sclerosis  explains  the  occurrence  of  hem- 
orrhage, but  the  only  evidence  in  support  of  this  sup- 
position is  the  occasional  association  of  the  two  con- 
ditions. Extensive  fat  necrosis  in  and  about  the 
pancreas,  destroying  wide  areas  of  adipose  tissue,  may 
cause  injury  to  the  walls  of  adjacent  vessels  and 
consequent  rupture,  but  rarely  is  the  necrosis  of  suffi- 
cient extent  to  afford  such  an  explanation.  The  relation 
of  fat  necrosis  to  lesions  of  the  pancreas  will  be  dis- 
cussed later,  when  it  will  be  shown  that  the  former  is 
secondary  to  the  latter. 

The  explanation  of  hemorrhage  secondary  to  inflam- 
matory changes  in  the  gland  has  been  much  discussed. 


VARIETIES    OF   ACUTE    PANCREATITIS. 


95 


Acute  inflammation  is  accompanied  by  escape  of  blood 
into  the  interstitial  tissue,  and  the  condition  has  been 
supposed  to  resemble  hemorrhagic  inflammation  in 
other  organs.  Inflammation  is  regarded  as  primary 
and  the  hemorrhage  its  consequence.  When  both  in- 
flammation and  hemorrhage  co-exist,  the  difficulty  of 
deciding  which  preceded  the  other  is'  obviously  great, 
— for  should  extensive  hemorrhage  occur,  proximity 
to  the  intestine  exposes  the  hemorrhagic  tissue  to 
infection  and  consequent  suppuration.  Both  hemor- 
rhage and  acute  inflammation  being  present,  it  is  not 
possible  to  determine  which  antedated  the  other. 
From  reports  of  cases  of  pancreatic  hemorrhage, 
moreover,  it  is  not  possible  to  decide  whether  hemor- 
rhage alone  had  occurred  or  both  inflammation  and 
hemorrhage  were  present  ;  for  on  the  one  hand 
in  few  cases  of  simple  hemorrhage  have  inflammatory 
changes  been  excluded  by  a  microscopical  examination, 
while  on  the  other  hand  the  diagnosis  of  inflammation 
in  many  instances,  as  in  a  few  of  the  cases  of  Fitz,  has 
been  based  upon  symptoms  observed  before  death. 

Seitz,  reviewing  the  cases  of  Loschner,  Oppolzer, 
Amidon,  Osier  and  Hughes,  Hirschberg  and  Birch- 
Flirschfeld,  finds  no  evidence  of  pancreatic  inflammation, 
and  concludes  that  inflammation  is  not  a  demonstrable 
cause  of  bulky  hemorrhage  into  the  organ. 

Under  certain  conditions,  which  the  foregoing  review 
leaves  ill-defined,  extensive  hemorrhage  occurs  into  the 


96  DISEASE   OF   THE   PANCREAS. 

substance  of  the  pancreas.  Atheroma  of  arteries  and 
fatty  degeneration  of  parenchyma  are  present  in  only 
a  limited  number  of  cases.  Since  in  some  instances 
there  is  no  evidence  of  inflammation,  while  in  others  in- 
flammation may  be  a  secondary  change  in  tissue  infil- 
trated with  blood,  it  is  obvious  that  no  sharp  line  can 
be  drawn  between  reported  cases  of  simple  hemorrhage 
and  those  of  hemorrhagic  inflammation. 

Experifnental  He^norrhagic  Pancreatitis. — Hemor- 
rhagic pancreatitis  has  been  produced  experimentally 
by  the  injection  of  a  variety  of  irritating  substances  into 
the  pancreas.  Thiroloix  injected  several  drops  of  del- 
iquescent chloride  of  zinc  into  the  duct  of  Wirsung  in 
a  dog.  Death  occurred  suddenly  after  a  short  interval, 
and  the  pancreas  was  represented  by  what  appeared  to 
be  a  blackish  clot.  Hlava  injected  artificial  gastric  juice 
into  the  pancreatic  duct.  This  fluid,  containing  hydro- 
chloric acid  in  the  proportion  of  one  to  one  thousand, 
caused  death  in  three  days  ;  the  pancreas  was  hyperse- 
mic  and  in  the  fat  of  the  omentum  and  of  the  mesen- 
tery were  numerous  foci  of  necroses.  Death  on  the 
tenth  day  followed  the  injection  of  five  cubic  centi- 
metres of  artificial  gastric  juice  with  hydrochloric  acid, 
four  to  one  thousand  ;  the  pancreas  was  the  seat  of 
hemorrhagic  infiltration  and  the  omentum  and  mesen- 
tery contained  foci  of  fat  necrosis.  He  suggests  that 
in  human  cases  hyperacid  gastric  juice  may  be  forced 
by  antiperistaltic  action  of  the  intestine  into  the  pan- 


VARIETIES    OF   ACUTE    PANCREATITIS.  97 

creatic  duct,  thus  causing-  the  condition.  Hlava  has 
produced  a  hemorrhagic  lesion  of  the  gland  by  injecting 
cultures  of  the  bacillus  coli  communis,  bacillus  lactis 
aerogenes,  and  bacillus  capsulatus  of  Friedlander,  but 
thinks  that  the  change  is  caused  by  the  acid  products 
of  these  organisms. 

By  the  injection  of  the  ferment,  papaine  (0.2  gramme  in 
thirty  cubic  centimetres  of  water),  into  the  pancreatic  duct 
of  a  dog,  Carnot  caused  the  death  of  the  animal  in  twenty- 
five  hours ;  the  pancreas  was  everywhere  infiltrated  with 
blood,  but  there  was  no  necrosis  of  fat.  Smaller  doses 
did  not  produce  hemorrhagic  lesions.  The  same  writer 
produced  hemorrhagic  pancreatitis  by  the  injection  of 
the  diphtheria  toxine  into  the  pancreatic  duct  of  a  rab- 
bit. A  suspension  of  the  bacillus  coli  communis  (twelve 
cubic  centimetres)  caused  a  similar  lesion  fatal  in  twenty- 
four  hours.  Subsequent  injections  of  the  same  organ- 
ism caused  inflammatory  changes  without  hemorrhage. 

More  varied  and  successful  experiments  have  been 
performed  by  Flexner.  In  ten  experiments  performed 
upon  dogs  hydrochloric  acid  varying  in  strength  in  dif- 
ferent instances  from  one-half  of  one  to  two  per  cent., 
and  in  amount  from  three  to  eight  cubic  centimetres, 
was  injected  into  the  pancreatic  duct.  In  six  instances 
there  resulted  hemorrhagic  inflammation  of  the  gland, 
accompanied  in  five  by  focal  fat  necrosis.  The  lesion 
was  characterized  by  hemorrhage,  necrosis  of  the  paren- 
chyma, and  accumulation  of  inflammatory  products.     In 

7 


98  DISEASE   OF   THE   PANCREAS. 

three  of  these  cases  death  followed  the  operation  within 
twenty-four  hours  ;  in  two  the  animals  were  killed.  In 
the  remaining  experiments  purulent  or  chronic  inter- 
stitial inflammation  resulted.  Hemorrhagic  lesions 
were  produced  in  two  dogs  by  the  use  of  nitric  acid 
(four  cubic  centimetres  of  a  two  per  cent,  solution  and 
five  cubic  centimetres  of  a  one  per  cent,  solution)  ;  in 
one  by  the  use  of  chromic  acid  (eight  cubic  centimetres  of 
a  one  per  cent,  solution).  In  a  second  series  of  experi- 
ments sodium  hydroxide  solution  (two  and  a  half  to 
five  cubic  centimetres  of  solutions  varying  in  strength 
from  one  to  two  per  cent.)  was  employed.  Hemor- 
rhagic lesions  resulted  in  three  cases  and  were  accom- 
panied by  fat  necrosis  in  at  least  two.  Suspensions  of 
bacteria  were  used  in  a  third  series.  Hemorrhagic  in- 
flammation was  caused  by  the  bacillus  pyocyaneus  and 
in  three  experiments  by  the  bacillus  diphtheriae,  but 
was  unaccompanied  by  definite  fat  necrosis.  In  two 
experiments  the  lesion  followed  the  injection  of  five 
cubic  centimetres  of  a  two  per  cent,  solution  of  formalin 
into  the  duct  and  was  associated  with  fat  necrosis. 
Flexner  and  Pearce  have  subsequently  shown  that  de- 
generation, hemorrhage,  and  emigration  of  leucocytes 
develop  with  great  rapidity,  occurring  within  one  to  two 
hours  after  the  introduction  of  such  an  irritant  as  arti- 
ficial gastric  juice. 

Etiology  of  Acute   Hemorrhagic   Pancreatitis, — The 
experiments    cited   show  that  a  variety  of  substances 


VARIETIES    OF   ACUTE    PANCREATITIS.  99 

injected  into  the  duct  of  the  pancreas  cause  hemor- 
rhagic inflammation.  How  far  they  can  be  used  to 
explain  the  pathogenesis  of  human  cases  is  doubtful. 
The  suggestion  of  Hlava  that  gastric  juice  may  be 
driven  by  antiperistaltic  action  of  the  intestine  into  the 
ducts  is  not  supported  by  any  evidence.  No  relation 
between  hemorrhagic  pancreatitis  and  bacterial  invasion 
from  the  intestine  has  been  demonstrated,  and  in  the 
cases  that  have  been  studied  no  orgfanism  has  been 
constantly  found. 

Dr.  Welch  cultivated  the  bacillus  coli  from  foci  of 
fat  necrosis  accompanying  acute  hemorrhagic  pan- 
creatitis, but  reached  the  conclusion  that  the  orgranism 
penetrated  the  dead  tissue  after  the  lesion  had  been 
produced.  In  cases  of  hemorrhagic  pancreatitis  Hlava 
found  the  bacillus  coli  associated  with  the  pneumococcus 
and  other  diplococci  ;  Cutler  and  Reynolds  and  Moore 
have  also  isolated  the  colon  bacillus.  Leonhard  in  one 
case  found  staphylococci,  streptococci,  and  two  uniden- 
tified bacilli,  while  Jackson  and  Ernst,  in  a  case  of  Fitz's, 
isolated  four  species  of  bacteria.  Ponfick  and  Marx 
each  cultivated  a  bacillus  closely  related  to  the  colon 
bacillus,  but  not  identical  with  it  nor  with  one  another. 
The  variable  and  inconstant  result  of  bacteriological 
examination  indicates,  as  almost  all  the  writers  cited 
agree,  that  these  various  organisms  are  not  the  etio- 
logical factor  in  producing  the  lesion,  but  are  merely 
secondary  invaders  of  injured  tissue. 


lOO  DISEASE    OF   THE    PANCREAS. 

The  etiology  of  hemorrhagic  inflammation  of  the 
pancreas  has  remained  obscure  until  a  series  of  cases 
recently  studied  has  demonstrated  a  relationship  be- 
tween the  lesion  and  cholelithiasis.  Since  the  common 
bile  duct  and  the  duct  of  Wirsung  unite  to  form  the 
diverticulum  of  Vater  before  they  reach  the  duodenum, 
changes  in  the  one  may  be  transmitted  to  the  other, 
thus  producing  secondary  lesions  of  the  liver  or  pan- 
creas. The  association  of  pancreatic  disease  with 
alterations  of  the  bile  passages  has  been  noted  by  a 
number  of  writers.  Korte,  in  his  monograph  upon 
the  surgery  of  the  pancreas,  mentions  the  fact  that 
diseases  of  the  bile  passages,  especially  cholelithiasis, 
are  frequently  associated  with  lesions  of  the  pancreas, 
and  thinks  it  probable  that  inflammation  can  extend 
from  the  bile  duct  to  the  gland.  Oser  makes  a  similar 
observation,  and  Lancereaux  cites  the  possibility  that  a 
gall-stone  lodged  in  the  common  duct  at  the  level  of 
the  diverticulum  may  occlude  the  pancreatic  duct  and 
produce  conditions  favorable  to  the  penetration  of 
micro-organisms  into  the  pancreas. 

The  Associatio7t  of  Acute  Pancreatitis  and  Choleli- 
thiasis.— My  attention  was  directed  to  the  relationship 
between  acute  pancreatitis  and  the  impaction  of  a 
calculus  in  the  common  bile  duct  by  the  following  case 
studied  at  autopsy  : 

Case  I. — L.  F.,  male,  aged  forty-seven  years,  was  admitted  to  the 
Johns  Hopkins  Hospital,  in  the  service  of  Dr.  Osier,  complaining  of 


VARIETIES    OF   ACUTE    PANCREATITIS.  loi 

abdominal  pain  and  fever.  He  had  suffered  with  somewhat  frequent 
attacks  of  indigestion,  characterized  by  pain  after  eating,  distention, 
and  rarely  nausea  and  vomiting,  but  otherwise  had  enjoyed  good 
health.  Six  months  before  his  present  illness  he  had  had  an  attack 
of  jaundice,  lasting  about  three  weeks,  and  accompanied  by  abdomi- 
nal pain  and  some  fever. 

The  present  illness  began  eighteen  days  before  admission  to  the 
hospital,  when  the  patient  was  suddenly  seized  with  violent  nausea 
and  vomiting,  accompanied  by  intense  cramp-like  pain  in  the  abdo- 
men. The  vomiting  continued  during  the  first  night,  and  had  since 
only  occasionally  recurred.  The  abdominal  pain,  which  was  not 
localized,  remained  severe  during  four  or  five  days,  and  at  times 
there  were  symptoms  of  collapse.  The  abdomen  was  distended  and 
the  bowels  were  constipated  until  the  fifth  day,  when,  with  the  aid 
of  a  purgative,  movement  occurred.  The  stool  was  normal  in  color. 
On  the  third  day  elevation  of  temperature  to  101.5°  ^-  ^^^  noted. 
About  the  seventh  day  tenderness  and  slight  swelling  were  noticed 
in  the  right  hypochondriac  region.  Since  this  time  the  patient  had 
an  irregular  temperature  (100°  to  103°  F.),  with  several  chills. 
After  the  first  few  days  abdominal  pain  and  tenderness  were  not 
severe,  but  distention  of  the  abdomen  gradually  increased.  Jaun- 
dice was  not  noted. 

Physical  Examination  (note  by  Dr.  Futcher). — The  conjunctivae 
have  a  slightly  yellow  cast.  On  inspection  of  the  abdomen  a  dis- 
tinct prominence  is  found  to  occupy  the  right  hypochondriac  and 
right  half  of  the  epigastric  region,  extending  into  the  upper  half  of 
the  umbilical  region.  Its  lower  margin,  which  descends  on  in- 
spiration, is  felt  in  the  median  line  at  the  level  of  the  umbili- 
cus. Its  right  border  cannot  be  sharply  defined,  but  in  the  median 
line  the  fingers  can  be  pressed  in  above  it.  Over  the  resistant  mass 
there  is  dull  tympany.  The  leucocytes  number  eighteen  thousand. 
The   urine  is    clear,   its    reaction  acid,  and  specific   gravity   1017. 


I02  DISEASE    OF   THE    PANCREAS. 

There  is  no  reduction  of  Fehling's  solution.  A  trace  of  albumin 
is  present. 

On  the  second  day  after  admission  a  stool  passed  was  of  golden 
yellow  color.  On  the  third  day  the  leucocytes  numbered  nineteen 
thousand  five  hundred,  and  the  temperature  varied  from  99.2°  to 
101.8°  F.  During  the  night  the  patient  was  irrational  at  times. 
The  temperature  rose  gradually,  reaching  a  maximum  of  104°  F.  A 
liquid  stool  of  ochre-yellow  color  was  passed.  The  urine  had  a 
specific  gravity  of  1020,  and  no  reaction  for  sugar  was  obtained. 

The  diagnosis  of  suppurative  pancreatitis  was  made  by  Dr.  Blood- 
good,  and  an  operation  for  its  relief  was  performed  under  cocaine 
anaesthesia.  A  linear  longitudinal  incision  was  made  below  the 
costal  margin  within  the  right  mammillary  line.  After  incising  the 
great  omentum  between  the  stomach  and  transverse  colon  an  abscess 
cavity  was  entered.  Grumous,  purulent  fluid  containing  necrotic 
particles  was  evacuated.  A  rubber  drainage-tube,  packed  about 
with  gauze,  was  inserted  into  the  wound.  After  operation  the  pulse 
remained  weak,  and  death  followed  at  the  end  of  about  four  hours. 
The  duration  of  the  fatal  illness  was  twenty-one  days. 

Autopsy. — Performed  three  hours  after  death.  The  body  is  that 
of  a  large-framed,  muscular  man  with  abundant  subcutaneous  fat. 
The  omentum,  which  contains  a  large  quantity  of  fat,  is  thickly 
studded  with  conspicuous  opaque,  white  areas,  usually  round,  and 
about  three  millimetres  in  diameter.  Similar  opaque,  white  areas 
are  present  in  the  fat  of  the  mesentery,  in  the  subperitoneal  fat  of 
the  anterior  abdominal  wall,  over  the  bladder,  over  the  kidneys, 
and  about  the  colon. 

The  drainage-tube  inserted  into  the  abdominal  wound  passes 
through  a  small  incised  opening  in  the  great  omentum  and  enters 
an  immense  abscess  cavity,  which  occupies  approximately  the  site 
of  the  lesser  peritoneal  cavity ;  the  foramen  of  Winslow  is  closed. 
The  walls  of  the  cavity  are  very  irregular  and  ragged,  and  have  a 


Fig.  12. — Gall-stones  from  Case  I,  (actual  size).     The  calculus  removed  from  the  common  bile 
duct  near  its  duodenal  orifice  is  placed  in  the  centre,  while  those  from  the  gall-bladder  surround  it. 


VARIETIES    OF   ACUTE    PANCREATITIS.  103 

necrotic  appearance,  in  general  opaque  and  gray,  occasionally  black. 
This  blackish-gray  appearance  extends  only  a  short  distance  below 
the  surface,  and  where  the  wall  is  formed  by  fat  gives  place  to 
numerous  foci  of  opaque,  white  color.  The  retroperitoneal  fat  in 
front  of  the  left  kidney  and  psoas  muscle  has  been  eroded,  and  an 
extension  of  the  cavity  passes  behind  the  jejunum  near  its  junction 
with  the  duodenum.  To  the  left  of  the  descending  part  of  the 
duodenum,  occupying  the  position  of  the  pancreas  and  projecting 
forward  into  the  abscess  cavity,  is  a  great  mass  of  black  material, 
necrotic  in  appearance,  extending  to  the  left  as  far  as  the  spleen. 
This  material  is  reddish-black  on  section,  somewhat  spongy  in  tex- 
ture, soft,  dry,  and  friable.  The  cavity  contains  at  least  five 
hundred  cubic  centimetres  of  fluid  reddish-gray  material,  in  which 
are  fat  droplets  and  black  necrotic  particles. 

The  liver  is  flaccid  in  consistence.  The  bile  ducts  are  slightly 
dilated,  and  contain  thin,  yellow  bile.  The  gall-bladder  is  bound 
by  numerous  adhesions  to  the  duodenum  and  stomach.  Its  walls 
are  thickened  and  it  is  much  distended,  containing  viscid,  yellow 
bile  and  more  than  one  hundred  brown,  faceted  calculi,  varying  in 
diameter  from  a  half  to  one  centimetre  (see  Fig.  12).  The  he- 
patic, cystic,  and  common  ducts  are  much  dilated.  On  opening 
the  duodenum  a  stone  is  felt  below  the  mucous  membrane,  situated 
in  the  common  bile  duct  near  its  termination.  It  is  seven  milli- 
metres in  diameter,  and  resembles  those  present  in  the  gall- 
bladder. The  pancreatic  duct  unites  with  the  common  bile  duct  at 
a  point  seven  millimetres  from  the  duodenal  orifice  The  pancreatic 
duct  is  not  distended.  The  pancreas  occupies  the  posterior  wall  of 
the  abscess  cavity  of  the  lesser  peritoneum,  and  is  covered  by  the 
mass  of  reddish-black,  friable  material,  changed  coagulated  blood, 
above  described.  The  organ  is  of  large  size,  and  the  glandular 
tissue  is  in  great  part  firm,  yellowish-white,  and  well  preserved. 
The  interstitial   tissue  has  a  dull  reddish,   in   places  hemorrhagic, 


I04 


DISEASE    OF   THE   PANCREAS. 


appearance,  and  contains  conspicuous  opaque,  yellow  areas  of  irreg- 
ular shape.  Where  the  anterior  surface  of  the  head  and  body  is  in 
contact  with  the  overlying  material  there  is  a  superficial  zone  of 
soft,  grayish,  necrotic  appearance. 

The  other  organs — heart,  lungs,  spleen,  stomach,  intestines,  and 
kidneys — present  no  noteworthy  alteration. 

Histological  JExamination. — The  interstitial  tissue  of  the  pancreas 
is  much  increased  and  wide  bands  of  fibrous  tissue  separate  groups 
of  lobules.  Numerous  irregularly  shaped  cells  filled  with  brownish- 
yellow  pigment  granules,  which  give  the  Prussian-blue  reaction  for 
iron,  afford  evidence  of  former  hemorrhage.  In  a  few  places  well- 
preserved  red  corpuscles  are  diffusely  scattered  in  the  tissue.  Foci 
of  necrotic  fat  are  present.  Many  acini  are  widely  dilated ;  their 
cells  are  flat  and  the  lumen  is  much  distended,  containing  products 
of  secretion  and  occasionally  one  or  more  polynuclear  leucocytes. 
In  an  area  corresponding  to  the  superficial  zone  of  necrotic  appear- 
ance before  mentioned,  nuclei  no  longer  stain,  and  the  architecture 
of  the  glandular  tissue  is  only  obscurely  distinguishable.  A  thick 
band  of  newly- formed  fibrous  tissue,  containing  an  occasional  acinus 
or  duct,  separates  the  necrotic  parenchyma  from  that  which  is  still 
intact.  The  mass  covering  the  pancreas  is  found  to  consist  of 
altered  blood ;  upon  and  immediately  below  its  surface  are  numerous 
polynuclear  leucocytes. 

Bacteriological  Examination. — Cultures  from  the  blood  contained 
in  the  heart,  from  the  lung,  and  from  the  liver,  studied  by  Mr.  V. 
H.  Bassett,  were  found  to  contain  the  bacillus  coli  communis.  A 
plate  culture  from  the  material  covering  the  pancreas,  and  forming 
part  of  the  abscess  wall,  contained  the  bacillus  coli  communis,  the 
bacillus  lactis  aerogenes,  and  the  bacillus  proteus  vulgaris. 

Anatotnical  Diagnosis. — Cholelithiasis ;  calculus  lodged  in  the 
common  bile  duct  near  its  orifice ;  slight  jaundice.  Old  hemorrhage 
within  and  about  the  pancreas,  with  localized  necrosis  and  chronic 


VARIETIES    OF   ACUTE   PANCREATITIS. 


105 


inflammation  ;  necrosis  of  fat  of  the  pancreas,  greater  and  lesser  omen- 
tum, mesentery,  and  subperitoneal  tissue  of  the  abdominal  wall ;  peri- 
pancreatic  abscess  limited  by  the  lesser  peritoneal  cavity.  Laparotomy 
wound. 

Symptoms  occurring  six  months  before  the  fatal 
illness  indicated  the  passage  of  a  calculus  along  the 
common  duct,  and  this  diagnosis  was  confirmed  at 
autopsy  by  the  presence  of  numerous  calculi  in  the 
gall-bladder.  The  second  attack  began  suddenly,  three 
weeks  before  death,  with  severe  nausea  and  vomiting, 
accompanied  by  intense,  cramp-like  pain  in  the  abdo- 
men. Tenderness  was  present  in  the  right  hypochon- 
driac region,  and  on  admission  to  the  hospital  the 
patient  was  slightly  jaundiced. 

Autopsy  disclosed  a  small  gall-stone  lodged  in  the 
common  bile  duct,  a  short  distance  from  its  orifice. 
The  lesser  peritoneal  cavity  was  the  site  of  an  abscess, 
the  walls  of  which  were  formed  in  large  part  by 
necrotic  fat ;  the  subperitoneal  tissue  was  studded 
with  conspicuous  opaque,  white  foci  of  fat  necrosis. 
The  pancreas  was  in  general  well  preserved,  but  its 
interstitial  tissue  was  increased  and  gave  evidence  of 
having  been  the  seat  of  hemorrhage.  The  anterior 
surface  of  the  pancreas  was  covered  by  a  considerable 
quantity  of  old,  clotted  blood,  having  the  dark  appear- 
ance of  gangrenous  tissue  and  forming  the  tumor  mass, 
which  was  palpable  during  life.  A  superficial  zone  of 
glandular  parenchyma  in  contact  with  this  material  was 


I06  DISEASE    OF    THE    PANCREAS. 

necrotic.  Since  jaundice  was  slight,  and  the  pancreatic 
duct  was  not  dilated,  it  is  probable  that  the  calculus 
produced  only  temporary  obstruction  of  the  two  ducts. 
I  have  been  able  to  collect  from  the  literature  a 
number  of  cases  in  which,  associated  with  hemorrhagic 
lesions  of  the  pancreas,  a  gall-stone  was  found  lodged 
in  the  common  duct  near  its  orifice,  or,  perhaps,  free 
in  the  duodenum,  the  common  duct  being-  dilated 
(Case  A).  In  the  latter  case  there  could  be  little  doubt 
that  it  had  shortly  before  occupied  the  first-named 
position. 

Case  A.  (Thayer. ) — During  sixteen  months  the  individual,  male, 
aged  sixty  years,  had  suffered  attacks  of  pain,  followed  by  jaundice. 
He  was  suddenly  attacked  with  severe  pain  in  the  left  hypochondriac 
and  epigastric  regions.  Collapse  preceded  death,  which  followed 
within  twenty-four  hours  after  the  onset  of  symptoms.  The  thick- 
ened gall-bladder  contained  over  a  hundred  calculi.  The  common 
bile  duct  was  dilated  to  the  size  of  the  little  finger,  and  in  the  duo- 
denum was  a  calculus  the  size  of  a  hazel-nut.  The  pancreas  was  large, 
grayish-pink,  mottled  with  reddish-brown.  The  surrounding  fat  was 
moderately  infiltrated  with  blood,  and  contained  foci  of  necrosis. 

Case  B.  (Day.) — For  several  months  the  patient,  male,  aged 
forty-nine  years,  had  suffered  with  pain  in  the  epigastrium,  at  times 
in  the  right  hypochondrium,  and  once  he  was  jaundiced.  About 
sixteen  hours  before  death  he  was  suddenly  attacked  with  vomiting 
and  severe  epigastric  pain,  followed  by  collapse.  ' '  The  gall-bladder 
contained  one  small  concretion  of  inspissated  bile ;  two  others  were 
lodged  in  the  duodenal  extremity  of  the  common  duct."  The 
body  and  tail  of  the  pancreas  were  enlarged  and  infiltrated  with 
blood.      In  the  neighborhood  of  the  gland  were  foci  of  fat  necrosis. 


VARIETIES    OF   ACUTE   PANCREATITIS. 


107 


Case  C.  (Dieckhoff. ) — No  clinical  history  is  given.  In  the  com- 
mon duct,  close  to  its  orifice,  was  a  gall-stone ;  others  were  present 
in  the  duct  behind  it  and  in  the  gall-bladder.  The  body  and 
tail  of  the  pancreas  were  beset  with  green  and  yellow  points,  the 
tail  being  almost  completely  necrotic.  Old  and  recent  hemor- 
rhages occurred.  Microscopical  examination  demonstrated  the  pres- 
ence of  suppurative  inflammation,  apparently  having  its  origin  in  the 
ducts. 

Case  D.  (Cutler.) — For  fifteen  years  the  patient,  a  woman, 
aged  fifty-eight  years,  had  suffered  with  severe  attacks  of  indigestion 
on  one  occasion  followed  by  jaundice  ;  pain  in  the  right  hypochon- 
driac region  occurred  during  later  attacks.  Four  days  before  death 
she  was  seized  with  pain  in  the  right  hypochondrium,  accompanied 
by  vomiting,  chill,  and  fever,  and  followed  by  jaundice.  A  small 
gall-stone  was  found  at  the  outlet  of  the  common  duct ;  others  were 
present  in  the  gall-bladder.  The  pancreas  was  enlarged,  surrounded 
and  infiltrated  with  blood.  Numerous  foci  of  fat  necrosis  were  seen 
in  its  neighborhood. 

Case  E.  (Kennan. ) — The  individual,  a  woman,  aged  thirty-eight 
years,  was  suddenly  seized  forty-two  hours  before  death  with  vomiting 
and  pain  in  the  upper  part  of  the  abdomen,  followed  by  symptoms 
of  collapse.  A  gall-stone,  about  the  size  of  a  pea,  was  found  pro- 
jecting from  the  orifice  of  the  common  duct  into  the  duodenum. 
Other  calculi  were  found  in  the  gall-bladder  and  common  bile  duct. 
The  pancreas  was  enlarged,  and  its  appearance  of  intense  injection 
was  evidently  due  to  inflammatory  change.  Slight  peritonitis  was 
present. 

Case  F.  (Simpson.) — The  patient,  male,  aged  forty-one  years,  was 
suddenly  attacked  with  vomiting  and  severe  abdominal  pain.  Col- 
lapse preceded  death,  which  occurred  at  the  end  of  forty-four  hours. 
A  small  cubical  gall-stone  projected  from  the  end  of  the  common  duct 
into    the    duodenum ;    similar  concretions  were   found   in  the  gall- 


I08  DISEASE    OF    THE    PANCREAS. 

bladder.  The  pancreas  was  greatly  enlarged,  weighing  five  hundred 
and  twenty-five  grammes,  and  was  mottled  with  areas  of  reddish-brown 
color,  due  to  hemorrhagic  infiltration  of  its  interstitial  tissue.  The 
organ  was  surrounded  by  semifluid,  clotted  blood,  of  dark-brown 
color.  The  intima  of  the  splenic  artery  was  of  a  dirty-blue  color, 
and  was  apparently  necrotic  about  two  centimetres  from  the  aorta ; 
the  writer  regards  this  vessel  as  the  source  of  the  hemorrhage,  although 
it  is  not  stated  that  rupture  had  occurred. 

In  the  preceding  seven  cases,  Case  I  included,  a 
calculus  had  lodged  in  the  common  bile  duct  near  its 
orifice,  or,  having  been  expelled  from  this  position  shortly 
before  death,  lay  in  the  duodenum,  leaving  the  common 
duct  dilated.  Necrosis  of  the  fat  in  or  about  the  pan- 
creas occurred  in  six  of  these  seven  cases  ;  in  the  report 
of  the  remaining  case  (F),  briefly  described  several  years 
after  its  occurrence,  no  reference  is  made  to  this  change. 

In  five  instances  recent  hemorrhages  had  occurred 
into  the  organ,  but,  microscopical  examination  being 
omitted,  it  is  difificult  to  determine  whether  these  cases 
should  be  classified  as  examples  of  simple  hemorrhage 
or  of  hemorrhagic  pancreatitis.  In  the  case  which  I  have 
recorded  there  was  evidence  of  past  hemorrhage  into 
and  about  the  pancreas,  accompanied  by  necrosis  of  a 
small  part  of  the  organ.  The  remainder  of  the  gland 
was  the  seat  of  chronic  interstitial  change,  and,  ap- 
parently as  the  result  of  invasion  of  micro-organisms 
into  the  hemorrhagic  and  necrotic  tissue,  an  abscess, 
limited  by  the  lesser  peritoneal  cavity,  had  formed  about 


VARIETIES   OF   ACUTE   PANCREATITIS.  109 

the  orean.  In  Case  C  there  were  old  and  recent  hemor- 
rhages  nito  the  pancreas,  which  had  undergone  suppura- 
tive inflammation  and  necrosis. 

Of  special  interest  are  the  cases  (A,  B,  E,  and  F) 
in  which  death  occurred  within  thirty-three,  sixteen, 
forty-two,  and  forty-four  hours  after  the  onset  of  sudden 
vomiting,  pain  in  the  upper  abdomen,  and  collapse. 
The  brief  duration  of  symptoms  indicates  that  the  cal- 
culus found  at  autopsy  had  been  lodged  only  a  short 
time  in  the  common  duct.  Nevertheless,  extensive 
lesion  of  the  pancreas,  hemorrhagic  in  character,  had 
resulted.  With  these  cases  it  is  impossible,  from  the 
data  recorded,  to  distinguish  between  hemorrhage  into 
the  pancreas  and  hemorrhagic  pancreatitis. 

The  preceding  cases  include  only  those  in  which 
there  is  positive  evidence  that  a  stone  passing  along  the 
common  bile  duct  had  become  impacted  in  such  a  posi- 
tion that  occlusion  of  the  pancreatic  duct  might  ensue. 
A  calculus  might  be  temporarily  so  located  and  cause 
severe  injury  to  the  gland,  but  finally,  being  expelled, 
give  no  evidence  of  its  former  impaction.  I  have  col- 
lected from  the  literature  (see  accompanying  table)  a 
number  of  cases  in  which  pancreatic  lesions  were  as- 
sociated with  cholelithiasis.  Gall-stones  were  found  in 
the  gall-bladder  or  gall-ducts,  but  except  in  Cases  i  to 
8  there  was  at  autopsy  no  convincing  evidence  that  a 
stone  in  the  common  bile  duct  had  occluded  the  pan- 
creatic duct. 


no 

DISEASE 

OF   THE    PANCREAS. 

CASES  OF  ACUTE  PANCREATITIS  WITH  CHOLELITHIASIS. 

No. 

Author. 

Duration. 

Pancreatitis. 

Remarks. 

I 

Thayer  (A)  . 

34  hours. 

Hemorrhagic. 

Calculus  in  duodenum. 

2 

Day(B)    .    . 

16  hours. 

Hemorrhagic. 

Calculi  in  common  duct. 

3 

Dieckhoff(C) 

Hemorrhagic,  gangre- 
nous, and  purulent. 

Calculus  in  common  duct. 

4 

Cutler  (D)    . 

4  days. 

Hemorrhagic. 

Calculus  in  common  duct. 

5 

Kennan    (E) 

42  hours. 

Hemorrhagic. 

Calculus  in  common  duct. 

6 

Simpson   (F) 

44  hours. 

Hemorrhagic. 

Calculus  in  common  duct. 

7 

Opie  (I)    .    . 

21  days. 

Hemorrhagic  and  gan- 
grenous. 

Calculus  in  common  duct. 

8 

Opie  (II).    . 

9  days 

Hemorrhagic. 

Calculus  in  common  duct. 

9 

Rolleston  .    . 

2  days. 

Hemorrhagic. 

lO 

Paul  .... 

30  hours. 

Hemorrhagic. 

II 

J.  A.  Smith  . 

24  hours. 

Hemorrhagic. 

12 

Kotschau  .    . 

48  hours. 

Hemorrhagic. 

13 

Chiari    .    .    . 

7  days. 

Gangrenous. 

Jaundice. 

14 

Chiari    .    .    . 

3  weeks. 

Gangrenous. 

Jaundice. 

15 

Mader   .    .    . 

13  days. 

Gangrenous. 

Jaundice. 

16 

Fitz    .... 

10  days. 

Gangrenous. 

Jaundice. 

'7 

Morian  .    .    . 

27  days. 

Hemorrhagic  and  gan- 
grenous. 

Jaundice. 

18 

Bryant  .    .    . 

4  days. 

Hemorrhagic. 

Jaundice. 

19 

Lund     .    .    . 

52  days. 

Hemorrhagic. 

Jaundice. 

20 

Lund 

7  days. 

Hemorrhagic. 

Jaundice. 

21 

Stockton  and 

Williams. 

7  days. 

Hemorrhagic  and  gan- 
grenous. 

Jaundice. 

22 

Struppler  .    . 

II  days. 

Gangrenous. 

Jaundice. 

23 

Habersohn    . 

4  months. 

Gangrenous. 

24 

Chiari    .    .    . 

2  months. 

Gangrenous. 

25 

Konig    .    .    . 

32  days. 

Gangrenous. 

26 

Korte     .    .    . 

4  months. 

Gangrenous. 

27 

Korte     .    .    . 

I  mcnth. 

Hemorrhagic  and  gan- 
grenous. 

28 

Fraenkel    .    . 

Gangrenous. 

29 

Fraenkel   .    . 

5  days. 

Hemorrhagic  and  gan- 
grenous. 

30 

Ehrich  .    .    . 

I  month. 

Gangrenous. 

31 

Scott  .... 

15  days. 

Gangrenous. 

32 

Grawitz      .    . 

32  days. 

Gangrenous. 

33 

Bryant   .    .    . 

5  days. 

Hemorrhagic. 

34 

Lund.    .    .    . 

16  days. 

Hemorrhagic  and  gan- 
grenous. 

35 

Hahn     .    .    . 

4  days. 

Hemorrhagic  and  gan- 
grenous. 

36 

Marx.    .    .    . 

4  days. 

Hemorrhagic. 

37 

Marx  .... 

4  days. 

Hemorrhagic. 

38 

Dieckhoff  .    . 

2  days. 

Purulent 

39 

Simon     and 
Stanley  .    . 

3  days. 

Purulent 

40 

Rolleston  .    . 

75  days. 

Purulent 

41 

Fuchs     .    .    . 

3  months. 

Purulent 

Calculus  in  common  duct. 

VARIETIES    OF   ACUTE   PANCREATITIS.  m 

The  first  eight  cases  of  the  table,  excluding  No.  8,  to 
be  described  later,  are  those  already  cited.  A  hemor- 
rhagic lesion  of  the  pancreas,  hemorrhage  or  hemor- 
rhagic pancreatitis,  was  present  in  cases  of  the  table 
Nos.  9,  lo,  II,  and  12.  Here  gall-stones  were  found  in 
the  gall-bladder  or  in  the  bile  passages,  but  there  is  no 
record  that  a  calculus  was  located  near  the  orifice  of  the 
common  duct.  Jaundice  was  absent,  and  the  autopsy 
gave  no  positive  evidence  that  a  stone  had  recently 
passed  into  the  duodenum.  Death  followed  within 
forty-eight  hours  the  onset  of  symptoms,  abdominal 
pain,  vomiting,  and  collapse.  The  clinical  and  path- 
ological picture  agrees  with  that  of  the  preceding  cases 
of  rapidly  fatal  hemorrhagic  lesion  (Nos.  i,  2,  5,  and  6). 
One  factor  alone  is  absent  the  offending  calculus  has 
apparently  been  passed  into  the  intestine  and  lost. 

The  table  includes  additional  cases  (Nos.  13  to  37), 
in  which  cholelithiasis  has  accompanied  hemorrhagic  or 
hemorrhagic  and  gangrenous  pancreatitis.  In  some  it 
is  not  improbable  that  the  co-existence  of  the  two  con- 
ditions may  have  been  accidental,  but  since  cases  of 
hemorrhagic  pancreatitis  recorded  in  the  literature  are 
not  numerous,  the  relative  frequency  with  which  gall- 
stones have  been  noted,  even  though  especial  attention 
has  not  been  given  them,  indicates  an  intimate  relation 
between  the  two  processes. 

In  four  cases  the  pancreas  was  the  seat  of  suppura- 
tive inflammation,  apparently  unassociated  with  hemor- 


112  DISEASE    OF   THE    PANCREAS. 

rhage  or  necrosis.  In  one  of  them  (No,  38)  a  gall- 
stone had  found  its  way  into  the  pancreatic  duct,  which 
was  dilated  to  accommodate  it.  Of  especial  interest 
is  Case  41,  recently  reported  by  Fuchs.  A  man  aged 
thirty-two  years,  who  had  had  recurring  abdominal  pain 
and  vomiting,  suffered  for  about  three  months  with 
repeated  attacks  of  great  severity,  on  one  occasion 
accompanied  by  jaundice.  Operation  disclosed  the 
presence  of  a  calculus  the  size  of  a  bean  situated  within 
the  diverticulum  of  Vater.  In  the  head  of  the  pancreas 
was  a  small  abscess.  Evacuation  of  the  abscess  and 
removal  of  the  calculus  were  followed  by  recovery. 
Hemorrhagic  or  hemorrhagic  and  gangrenous  pancrea- 
titis, as  in  the  somewhat  similar  Cases  i  to  8,  may  have 
preceded  the  formation  of  an  abscess. 


CHAPTER   V. 

THE  ETIOLOGICAL  RELATION  OF  GALL-STONES  TO  ACUTE 
HEMORRHAGIC  PANCREATITIS.  HEMORRHAGIC  AND  GAN- 
GRENOUS   PANCREATITIS. 

The  case  previously  described,  together  with  those 
found  in  the  Hterature,  suggest  no  process  nor  mechan- 
ism by  which  a  lesion  of  the  pancreas  results  from  the 
presence  of  a  calculus  in  the  common  bile  duct  near 
its  duodenal  orifice.  The  autopsy  upon  a  second  case 
of  acute  hemorrhagic  pancreatitis  studied  in  the  par- 
tial light  of  that  previously  cited  has  demonstrated  a 
mechanism  by  which  a  small  biliary  calculus  produces  a 
destructive  lesion  of  the  pancreas  and  at  the  same  time 
has  brought  our  knowledge  of  the  lesion  into  correla- 
tion with  facts  demonstrable  by  experimental  means. 

Case  II.  ^ — Mr.  T.,  a  corpulent  man  of  robust  appearance,  aged 
forty-eight  years,  had  been  for  several  years  subject  to  attacks  of 
"indigestion"  accompanied  by  pain  in  the  epigastrium.  After 
luncheon,  nine  days  before  the  fatal  termination  of  his  illness,  he  was 
suddenly  seized  with  severe  pain  in  the  abdomen,  accompanied  by 
nausea.  The  pain  disappeared,  but  returned  at  the  end  of  twenty- 
four  hours.     After  drinking  large  quantities  of  water,   the  patient 

^  The  clinical  history  of  this  case  has  been  reported  by  Dr.  Hal- 
sted.  In  the  "Bulletin  of  the  Johns  Hopkins  Hospital,"  1901,  xii. 
182,  I  described  the  mechanism  by  which  a  biliary  calculus  causes 
acute  hemorrhagic  pancreatitis. 

8  '  113 


114 


DISEASE    OF   THE    PANCREAS. 


with  difficulty  forced  himself  to  vomit.  The  pain  persisted,  but 
during  the  week  following  he  took  his  meals  regularly  and  slept  as 
usual.  About  noon  of  the  day  preceding  his  admission  to  the  hospital 
the  pain  became  so  severe  that  the  repeated  administration  of  morphia 
gave  little  relief.  When  seen  at  nine  o'clock  in  the  evening  he  was 
able  to  walk,  though  in  great  pain ;  his  pulse  was  full  and  regular. 
The  epigastrium  was  tender  on  pressure ;  the  skin  was  markedly  cya- 
nosed.  The  following  morning  he  w^as  taken  to  the  Johns  Hopkins 
Hospital,  and  at  eleven  a.m.  an  operation  w'as  performed  by  Dr. 
Halsted. 

On  opening  the  abdomen  in  the  middle  line  blood-stained  fluid 
escaped.  Numerous  foci  of  fat  necrosis  were  seen  upon  the  omen- 
tum, in  the  mesentery,  and  along  the  lesser  curvature  of  the  stomach* 
The  pancreas  was  examined  through  an  opening  made  in  the  gastro- 
colic omentum,  and  the  tissue  over  it  was  found  infiltrated  with 
blood-stained  fluid.  Slight  distention  of  the  common  bile  duct  was 
noted.  Fluid  in  the  abdominal  cavity  was  removed,  and  gauze, 
packed  through  the  wound,  was  brought  into  contact  with  the  head 
of  the  pancreas.      Death  occurred  twenty-three  hours  later. 

Autopsy. — The  body,  still  warm,  is  that  of  a  large  man  with  very 
abundant  subcutaneous  fat.  The  peritoneal  cavity  contains  a  moderate 
excess  of  blood-stained  serous  fluid.  Fat  is  present  in  large  amount  in 
the  omentum,  mesentery,  and  subperitoneal  tissue,  and  is  thickly  stud- 
ded with  small,  usually  round,  opaque,  white  areas  of  necrosis,  often 
surrounded  by  a  narrow  zone  of  injection.  They  are  most  abundant 
in  the  omentum  and  in  the  retroperitoneal  fat  adjacent  to  the  pancreas. 

The  pancreas  is  represented  by  a  blackish  swollen  mass  extending 
from  the  descending  part  of  the  duodenum  to  the  spleen.  The  fat 
in  contact  with  its  splenic  end  has  a  similar  blackish  color,  and  is  soft 
and  friable.  The  pancreas  is  greatly  increased  in  size  and  is  irregu- 
larly cylindrical  in  shape.  The  anterior  surface  is  smooth,  and  has 
an  almost  uniform  black  or  reddish-black  color.     On  section  the  gland- 


ETIOLOGY    OF   ACUTE   PANCREATITIS. 


115 


ular  substance  is  found  to  be  in  great  part  transformed  into  material 
of  similar  color.  The  head  of  the  organ  for  a  distance  of  two  and 
a  half  centimetres  from  the  duodenum  is  normal  in  appearance,  but 
tissue  which  is  in  immediate  contact  with  this  well-preserved  gland 
substance  is  soft  and  black  in  color,  mottled  here  and  there  with 
small  areas  of  dull  red.  The  distal  half  of  the  organ  shows  a  similar 
mottling  of  black  and  reddish  areas,  among  which  are  islands  of  yellow- 
ish, relatively  well-preserved  tissue.  On  opening  the  splenic  vein  where 
it  lies  in  contact  with  the  pancreas,  the  intima  is  found  to  have  a 
mottled  yellow,  blackish,  and  red  appearance,  due  to  changes  in  the 
underlying  tissue.  Occupying  the  lumen  is  a  mixed  red  and  yellow 
thrombus  mass,  firm  in  consistence  and  adherent  to  the  intima. 

The  duodenum  was  opened  and  the  common  orifice  of  the  bile 
and  pancreatic  ducts  examined.  The  papilla  is  prominent,  but  its 
orifice  is  of  small  size,  measuring  one  millimetre  in  diameter.  The 
common  bile  duct,  which  near  its  termination  is  completely  embedded 
in  the  substance  of  the  pancreas,  is  slightly  distended.  The  gall- 
bladder when  opened  is  found  to  contain  a  moderate  amount  of 
viscid,  blackish  bile  ;  no  concretions  are  present.  The  termination 
of  the  pancreatic  duct,  which  is  surrounded  by  the  well-preserved 
pancreatic  substance  in  contact  with  the  duodenum,  was  exposed  by 
dissection,  and  found  to  unite  with  the  common  bile  duct  ten  milli- 
metres from  the  summit  of  the  bile  papilla.  A  probe  passed  into  the 
common  duct  is  stopped  four  millimetres  from  the  duodenal  orifice, 
and  cannot  be  touched  with  a  second  probe  in  contact  with  the  nar- 
row orifice.  Examination  discloses  a  small  gray-white,  very  firm 
concretion,  three  millimetres  in  diameter,  tightly  impacted  in  the 
diverticulum  of  Vater,  from  which  it  cannot  escape  through  the 
narrow  duodenal  opening.  The  pancreatic  duct  and  its  larger 
branches,  where  they  traverse  the  intact  tissue  of  the  head,  are 
stained  bright  green  with  bile. 

In  the  liver  are  found   portal  veins  distended  and  plugged  with 


Il6  DISEASE    OF   THE    PANCREAS. 

red  thrombi  which  probably  have  had  their  origin  in  emboli  from  the 
thrombosed  splenic  vein.  The  heart,  lungs,  spleen,  kidneys,  and 
adrenal  glands  present  no  noteworthy  abnormality.  The  urine  con- 
tained in  the  bladder  does  not  reduce  Fehling's  solution. 

Microscopic  Exa?nination  of  the  Fa?icreas. — A  section  passing 
through  the  line  of  demarcation  between  intact  parenchyma  in  the 
head  of  the  gland  and  the  adjacent  necrotic  tissue  shows  a  very 
abrupt  transition  from  the  one  to  the  other.  On  the  one  side  the 
pancreatic  acini  are  well  preserved,  the  secreting  cells  are  normal  in 
appearance  and  their  basal  zone  stains  deeply  with  haematoxylin, 
while  islands  of  Langerhans  are  fairly  abundant  and  appear  to  be 
normal.  The  loose  interlobular  areolar  tissue  is  everywhere  infil- 
trated with  red  blood-corpuscles  ;  polynuclear  leucocytes  are  present 
in  large  numbers  and  often  form  collections  of  considerable  extent. 
Within  the  margin  of  the  intact  tissue  are  several  small  areas  where 
the  parenchyma  presents  an  early  stage  of  necrosis.  Here  the  se- 
creting cells  no  longer  stain  with  hsematoxylin,  but  assume  a  homo- 
geneous clear  pink  color  with  eosin ;  the  nuclei  which  are  still  pre- 
served are  much  smaller  than  those  of  the  normal  cells,  and  unlike 
the  latter  are  irregular  and  distorted,  and  stain  homogeneously. 
Small  hemorrhages  have  taken  place  into  the  interacinar  tissue  of  such 
an  area,  and  polynuclear  leucocytes  are  present  in  moderate  number. 
Nearby,  in  similarly  localized  areas,  the  process  is  more  advanced, 
and  the  parenchymatous  cells  are  replaced  by  formless  material  which, 
staining  faintly,  is  mingled  with  a  few  nuclear  fragments  and  is 
densely  infiltrated  with  polynuclear  leucocytes  and  red  blood-cor- 
puscles. 

The  transition  from  relatively  normal  parenchyma  containing  a 
few  islands  of  necrosis  to  wholly  necrotic  tissue  is  very  abrupt  and  is 
marked  by  a  zone  composed  of  nuclear  fragments,  polynuclear  leuco- 
cytes, red  blood-corpuscles,  and  fibrin.  That  part  of  the  section 
which  corresponds  to  the  black  and  reddish-black  material  seen  mi- 


ETIOLOGY    OF   ACUTE   PANCREATITIS. 


117 


croscopically  is  necrotic,  nuclei  are  no  longer  present,  and  though 
the  architecture  of  the  gland  is  still  obscurely  definable,  both  paren- 
chyma and  connective  tissue  have  a  dark-brown  discoloration  due  to 
the  presence  of  brown  pigmented  material  which  appears  to  be 
changed  blood. 

In  sections  stained  by  Weigert's  method  for  the  demonstration  of 
fibrin  was  noted  a  histological  detail  inconspicuous  by  other  methods. 
Capillary  vessels  in  the  living  tissue  near  the  margin  of  necrosis,  as 
well  as  in  the  immediately  adjacent  necrotic  part,  have  undergone 
hyaline  thrombosis  and  form  conspicuous  deep-blue,  often  branched 
lines,  as  though  injected.  Examination  with  high  magnification 
demonstrates  at  times  a  close  mesh-work  of  fibrin  in  these  vessels. 
In  sections  stained  with  haematoxylin  and  eosin  their  contents  take  a 
homogeneous  bright  pinkish-red  stain,  and  red  blood-corpuscles  are 
no  longer  seen,  as  in  adjacent  capillaries. 

In  sections  stained  for  bacteria  with  methylene-blue,  with  gentian 
violet,  and  by  Weigert's  method,  none  were  discovered. 

Bacteriological  Examination. — Plate  cultures  in  agar-agar  were 
made  at  autopsy  from  the  heart's  blood,  peritoneal  cavity,  pancreas 
(aerobic  and  anaerobic  on  hydrocele  agar-agar),  gall-bladder,  liver, 
spleen,  and  kidney.  They  have  been  studied  by  Mr.  V.  H.  Bassett, 
to  whom  I  am  indebted  for  the  following  report.  Cultures  from  the 
heart's  blood,  spleen,  and  gall-bladder  give  negative  results.  The 
anaerobic  culture  from  the  pancreas  shows  no  growth  after  an  incu- 
bation of  seventy-two  hours.  The  aerobic  agar-agar  plate  from  the 
pancreas  contains  at  the  end  of  twenty-four  hours  a  single  superficial 
colony  of  a  pigment  forming  coccus  of  which  the  cultural  characters 
indicate  that  it  is  a  contamination  from  the  air.  Streptococcus  py- 
ogenes and  staphylococcus  epidermis  albus  were  isolated  from  the 
peritoneal  cavity.  The  colon  bacillus  was  present  in  cultures  from 
the  liver  and  kidney. 

Anatomical  Diagnosis. — Cholelithiasis;   calculus  impacted  in  the 


Il8  DISEASE    OF   THE    PANCREAS. 

diverticulum  of  Vater,  partially  filling  it,  and  occluding  its  duodenal 
orifice.  Acute  hemorrhagic  pancreatitis ;  disseminated  abdominal 
fat  necrosis.  Partial  thrombosis  of  the  splenic  vein;  embolism  and 
thrombosis  of  branches  of  the  portal  vein. 

The  preceding  autopsy  has  disclosed  a  condition 
which  explains,  I  believe,  the  pathogenesis  of  those 
cases  of  acute  hemorrhagic  and  gangrenous  pancreatitis 
which  are  associated  with  gall-stones.  The  diverticulum 
of  Vater  was  ten  millimetres  in  leno-th.  Lodged  at  its 
apex,  blocking  the  duodenal  orifice,  was  a  small  calculus 
only  three  millimetres  in  diameter,  but  too  small  to 
pass  the  narrow  opening.  Though  it  occluded  the 
duodenal  orifice  of  the  diverticulum,  it  was  so  small  that 
the  orifices  of  the  common  bile  duct  and  the  pancreatic 
duct  were  unobstructed.  The  two  ducts  were,  there- 
fore, converted  into  a  continuous  closed  channel  from 
which  it  was  not  possible  for  either  bile  or  pancreatic 
juice  to  escape  (see  Fig.  8,  i.,  page  40). 

On  dissecting  the  pancreatic  duct  where  it  passed 
through  the  unchanged  parenchyma  in  contact  with  the 
duodenum  it  was  found,  like  the  bile  duct,  to  be  stained 
bright  green  with  bile.  Where,  as  in  this  case,  the 
two  ducts  become  a  closed  channel,  the  entrance  of 
bile  into  the  pancreas  or  of  pancreatic  juice  into  the 
bile  passages  would  depend  upon  the  relative  pressure 
in  the  two  ducts.  The  pressure  at  which  bile  and  pan- 
creatic juice  are  secreted  being  small,  any  slight  differ- 
ence that  might  exist  would  be  overcome  by  the  gall- 


ETIOLOGY    OF   ACUTE    PANCREATITIS.  119 

bladder,  a   muscular   organ   which  at  intervals   forces 
bile  in  considerable  quantity  along  the  common  duct. 

A  small  calculus  only  partially  filling  the  ampulla  of 
Vater  can  convert  the  two  ducts  into  a  continuous 
channel,  while  a  larger  stone  might  simultaneously, 
obstruct  the  duodenal  orifice  of  the  diverticulum  and 
the  orifices  of  the  two  ducts  which  enter  it,  thus  dam- 
ming back  bile  and  pancreatic  juice  upon  their  respec- 
tive glands.  In  the  present  case,  as  previously  men- 
tioned, the  diverticulum  measured  ten  millimetres  in 
leneth,  the  calculus  three  millimetres  in  diameter.  In 
many  cases  of  hemorrhagic  and  of  hemorrhagic  and 
gangrenous  pancreatitis  gall-stones  found  in  the  gall- 
bladder and  bile  passages  at  autopsy  have  been  small 
and  are  often  described  as  pea-sized.  Such  statements 
are  made  in  the  reports  of  Day,  Cutler,  Kennan,  Simp- 
son, Chiari  (two  cases).  Smith,  Ehrich,  Fraenkel,  Korte, 
Morian,  Rolleston,  Grawitz,  Opie  (two  cases),  Bryant, 
and  Lund  (three  cases). 

Anatomical  peculiarities  of  the  diverticulum  of  Vater 
favor  or  prevent  conversion  of  the  two  ducts  into  a 
closed  channel.  The  diverticulum  may  be  regarded  as 
a  somewhat  conical  cavity  into  the  base  of  which  open 
the  bile  and  pancreatic  ducts  ;  the  apex  of  the  cone 
situated  at  the  summit  of  the  bile  papilla  is  the  com- 
mon duodenal  orifice  of  both  ducts.  It  has  been  previ- 
ously shown  that  in  a  considerable  number  of  individ- 
uals, about  one  in   ten,  the  two  ducts  open  separately 


I20  DISEASE    OF   THE   PANCREAS. 

into  the  intestine  and  no  diverticulum  exists  (see  Fig. 
8,  ii.).  Variations  to  which  the  diverticulum  is  subject 
have  been  considered  (page  39  et  seq.)  ;  in  one  hundred 
instances  its  length  varied  from  zero  to  eleven  millime- 
tres, and  in  only  thirty  of  these  did  the  length  reach 
five  millimetres.  The  averaofe  diameter  of  the  duode- 
nal  orifice,  measured  in  seventy-five  instances,  was 
two  and  a  half  millimetres.  In  twenty-one  individuals 
the  diameter  of  the  orifice  was  equal  or  greater  than 
the  length  of  the  diverticulum,  and  it  is  obviously  im- 
possible that  a  calculus  assumed  to  be  approximately 
spherical  could  lodge  in  the  orifice  and  only  partially 
occlude  the  cavity.  Indeed,  if  possible  distention  of 
the  orifice  be  considered,  it  is  hardly  probable  that  a 
small  calculus  could  lodge  in  the  opening,  yet  only 
partially  fill  the  cavity,  unless  the  length  of  the  diver- 
ticulum should  exceed  the  diameter  of  the  orifice  by 
several  millimetres.  Since  in  only  thirty-two  of  one 
hundred  instances  does  the  length  of  the  diverticulum 
exceed  five  millimetres,  the  average  diameter  of  the 
orifice  being  two  and  a  half  millimetres,  it  is  probable 
that  in  little  more  than  three  of  ten  individuals  are  the 
anatomical  conditions  such  that  a  small  calculus  might 
divert  the  bile  into  the  pancreatic  duct.  Moreover,  it 
must  be  remembered,  in  one  of  ten  cases  the  bile  duct 
joins  the  smaller  pancreatic  duct,  while  the  larger  duct 
of  Santorini  enters  the  duodenum  at  the  site  of  the 
lesser  papilla.     These  facts  explain  in  part  the  rarity  of 


ETIOLOGY    OF   ACUTE    PANCREATITIS.  121 

acute  hemorrhagic  pancreatitis  when  compared  with  the 
relative  frequency  of  cholelithiasis. 

Effect  of  Bile  Injected  into  the  Pancreatic  Duct. — 
Experiments  previously  described  in  detail  have  shown 
that  a  variety  of  irritating  substances,  various  acids  and 
alkalies,  artificial  gastric  juice,  suspensions  of  bacteria, 
etc.,  injected  into  the  pancreatic  duct  cause  hemor- 
rhagic inflammation  of  the  gland.  Cases  just  described 
have  demonstrated  in  association  with  acute  hemor- 
rhagic pancreatitis  a  mechanism  by  which  a  small  biliary 
calculus  diverts  bile  into  the  pancreatic  duct.  A  series 
of  experiments  was  undertaken  in  order  to  deter- 
mine the  effect  of  bile  thus  brought  into  contact  with 
the  pancreatic  parenchyma.  The  duodenum  of  dogs 
was  opened  for  a  distance  of  several  centimetres  oppo- 
site the  larger  pancreatic  duct.  The  blunt-pointed  nozzle 
of  a  syringe  was  inserted  into  the  orifice  of  the  duct, 
and  bile  obtained  from  the  same  or  from  a  second  dog 
was  injected  into  the  organ.  The  operations  were  per- 
formed with  the  usual  antiseptic  precautions,  and  the 
duodenal  wound  was  closed  by  submucous  mattress 
sutures.  The  results  were  almost  uniform.  Several 
experiments  ^  exhibiting  features  repeated  in  the  others 
will  be  described  in  detail. 


'  These  experiments  have  been  described  in  the  ' '  Bulletin  of  the 
Johns  Hopkins  Hospital,"  1901,  xii.  182.  The  experiments  here 
quoted  are  designated  by  the  numbers  used  in  that  article. 


122  DISEASE    OF   THE    PANCREAS. 

Experiment  2. — Bile  (five  cubic  centimetres)  from  a  dog  was  in- 
jected into  the  larger  pancreatic  duct  of  a  second  dog.  The  animal 
was  killed  at  the  end  of  five  days.  In  the  omental  fat  are  several 
opaque  white  areas  of  fat  necrosis,  while  near  the  splenic  extremity 
of  the  pancreas  are  several  inconspicuous  foci  of  a  similar  nature. 
In  the  duodenal  part  of  the  gland,  in  the  neighborhood  of  the 
orifice  of  the  larger  duct,  for  a  distance  of  three  and  a  half  cen- 
timetres, there  is  extensive  hemorrhagic  infiltration  separating  islands 
of  parenchyma.  In  places  the  gland  substance  is  soft  and  of  gray 
necrotic  appearance.  The  splenic  part  is  firm  in  consistence,  and 
at  several  points  are  areas  of  hemorrhagic  infiltration.  Microscopic 
examination  of  sections  from  the  hemorrhagic  duodenal  part  shows 
wide  areas  of  necrosis  implicating  both  lobular  and  interstitial  tissue. 
The  parenchymatous  cells  are  hyaline  and  without  nuclei.  Copious 
hemorrhage  has  taken  place  into  these  areas,  and  at  the  margin  of 
intact  tissue  polynuclear  leucocytes  are  numerous.  Fibrin  is  abun- 
dant in  the  necrotic  interlobular  tissue.  Where  wide-spread  de- 
struction has  not  occurred  there  has  been  active  proliferation  of 
interstitial  tissue,  replacing  in  part  destroyed  parenchyma  and  con- 
taining numerous  red  blood-corpuscles  and  polynuclear  leucocytes. 
The  remaining  acini  are  often  separated  by  newly-formed  interstitial 
tissue,  and  there  is  the  appearance  of  advanced  chronic  inflammation. 

Experiment  3. — After  opening  the  duodenum  of  a  dog,  five  cubic 
centimetres  of  bile  obtained  from  a  second  animal  were  injected  into 
the  pancreatic  duct.  Death  followed  within  twenty  hours.  The  peri- 
toneal cavity  contains  several  cubic  centimetres  of  bloody  fluid  and 
the  peritoneal  surface  has  an  irregularly  distributed,  deep  red  injection. 
The  entire  omentum  is  studded  with  conspicuous  opaque  white  areas 
of  fat  necrosis.  In  the  mesentery  of  the  duodenum,  near  the  pan- 
creas, they  are  numerous,  and  are  also  present  in  the  retroperitoneal 
fat  and  in  the  properitoneal  fat  below  the  diaphragm.  The  splenic 
arm  and  the  upper  half  of  the  attached  duodenal  part  of  the  pan- 


ETIOLOGY    OF   ACUTE    PANCREATITIS. 


123 


creas  are  swollen  and  cedematous  in  appearance,  and  the  lobules 
are  separated  by  tissue  infiltrated  with  blood.  The  cut  surface  has 
a  mottled  dull  red  and  gray  color,  the  interstitial  tissue  being  hemor- 
rhagic, while  minute  hemorrhages  are  in  places  seen  within  the  lob- 
ular substance.  Microscopic  examination  shows  that  the  dull  red 
areas  in  the  pancreas  seen  macroscopically  represent  foci  of  necrosis 
where  parenchymatous  cells  stain  only  with  eosin  and  no  longer  con- 
tain nuclei.  The  blood-vessels  here  are  widely  dilated,  and  abun- 
dant hemorrhage  has  frequently  taken  place.  Polynuclear  leucocytes 
are  present,  but  are  not  very  numerous.  Such  an  area  of  necrosis 
and  hemorrhage  is  at  times  limited  to  the  central  part  of  a  lobule 
group,  while  the  acini  farther  from  the  central  duct  are  intact.  The 
interstitial  tissue,  particularly  in  the  duodenal  part  of  the  gland,  has 
an  cedematous  appearance,  and  contains  red  blood-corpuscles,  poly- 
nuclear leucocytes,  and  fibrin. 

Should  bile  enter  the  pancreas  after  occlusion  of 
the  distal  end  of  the  diverticulum  of  Vater,  its  only- 
opportunity  for  escape  would  be  by  way  of  the  lesser 
pancreatic  duct.  In  order  to  reproduce  this  condition, 
in  two  experiments  the  duodenum  was  not  opened,  but 
the  duct  was  exposed  where  it  approaches  the  intestine, 
ligated  close  to  the  duodenum,  and  partially  cut  across. 
By  means  of  a  syring-e  with  a  blunt  nozzle  bile  was 
injected  into  the  distal  end  of  the  duct,  which  was  then 
ligated. 

Experiment  6. — Into  the  larger  duct  was  injected  five  cubic  cen- 
timetres of  bile  obtained  by  puncture  from  the  dog's  gall-bladder. 
The  animal  died  twenty-four  hours  later.  Opaque,  white  areas  of 
fat  necrosis  are  numerous  upon  the  surface  of  the  duodenal  part  of 


124  DISEASE    OF   THE   PANCREAS. 

the  pancreas  and  in  the  immediately  adjacent  fat  of  the  duodenal 
mesentery,  and  are  present  in  both  layers  of  the  omentum.  The 
parenchyma  throughout  the  gland  is  mottled,  small  dull-red  areas 
alternating  with  more  normal  gray-yellow  glandular  substance,  this 
hemorrhagic  appearance  of  the  parenchyma  being  most  marked  in 
the  duodenal  part  of  the  gland.  Microscopic  examination  of  all 
parts  of  the  pancreas  shows  the  presence  of  numerous  foci  of  necrosis. 
The  gland  cells  have  assumed  a  hyaline  appearance  and  have  lost 
their  nuclei.  The  blood-vessels  in  these  areas  are  widely  distended, 
and  at  times  there  is  abundant  extravasation  of  red  blood-corpuscles. 
Polynuclear  leucocytes  in  moderate  number  are  seen  between  the 
necrotic  cells.  The  interlobular  tissue  is  in  many  places  much  dis- 
tended, containing  red  blood-corpuscles,  polynuclear  leucocytes,  and 
fibrin. 

The  injection  of  five  cubic  centimetres  of  bile  into  the 
pancreatic  duct  caused  hemorrhagic  inflammation  of 
the  gland  in  four  dogs,  two  of  which  died  within 
twenty-four  hours  after  the  operation.  In  these  ex- 
periments death  did  not  follow  the  use  of  smaller 
amounts,  and  the  changes  produced  in  the  organ  were 
less  wide-spread  and  severe.  In  every  case  necrosis 
of  the  adjacent  fat  accompanied  the  lesion  of  the 
pancreas,  and  in  two  instances  in  which  death  occurred 
spontaneously  foci  of  the  necrosis  were  abundant  and 
disseminated. 

These  experiments  have  demonstrated  the  possibility 
of  reproducing  in  animals  by  means  of  bile  the  hemor- 
rhagic lesion  which  occurs  in  human  cases.  They  afford 
additional  evidence  that  bile  diverted  into  the  pancreatic 


ETIOLOGY   OF   ACUTE    PANCREATITIS.  125 

duct  by  a  biliary  calculus  is  capable  of  producing  the 
lesion  of  acute  hemorrhagic  pancreatitis. 

Frequency  with  which  Acute  Heinorrhagic  Pancreatitis 
is  Produced  by  Biliary  Calculi. — While  the  etiology  of 
many  cases  of  hemorrhagic  pancreatitis  is  thus  estab- 
lished, it  cannot  be  demonstrated  that  all  are  dependent 
upon  the  passage  of  a  gall-stone  along  the  common 
bile  duct.  In  the  following  case  neither  the  clinical 
history  nor  the  autopsy  affords  any  evidence  of  choleli- 
thiasis. A  complete  autopsy  was  not  permitted,  and 
the  possibility  cannot  be  excluded  that  a  single  small 
calculus  producing  the  lesion  escaped  into  the  intestine. 

Case  III. — The  patient,  a  man,  twenty -eight  years  of  age,  had, 
before  his  fatal  illness,  been  in  good  health.  There  was  no  history 
of  any  previous  digestive  disturbance,  and  he  had  never  been  jaun- 
diced. His  illness  began  four  days  before  death  with  an  attack  of 
nausea  and  vomiting,  coming  on  shortly  after  a  meal.  About  an 
hour  later  he  was  attacked  with  agonizing  pain  in  the  epigastric 
region,  and  the  vomiting  continued  during  the  night,  but  in  the 
morning  became  less  severe.  The  following  day  he  suffered  with  vio- 
lent hiccough,  which  continued  until  the  time  of  operation.  When 
admitted  to  the  hospital  he  seemed  ill  and  vomited  almost  con- 
tinuously. Examination  of  the  abdomen  showed  nothing  except 
distention  in  the  neighborhood  of  the  umbilicus.  An  exploratory 
laparotomy  was  performed  by  Dr.  J.  F.  Mitchell,  and  innumerable  foci 
of  fat  necrosis  were  found  studding  the  omentum.  The  lesser  perito- 
neal cavity  contained  bloody  fluid,  and  the  pancreas  was  covered 
by  a  coagulum  of  blood.  The  abdomen  was  closed,  a  gauze  drain 
being  inserted  into  the  wound.  The  patient  died  twenty-four  hours 
later. 


126  DISEASE    OF   THE    PANCREAS. 

Autopsy. — An  examination  of  the  abdominal  contents  through  the 
wound  was  permitted,  and  it  was  possible  to  remove  only  the  pan- 
creas with  the  gall-bladder  and  a  part  of  the  duodenum.  The 
pancreas  was  of  great  size,  weighing  one  hundred  and  ninety- 
grammes  ;  the  head  and  tail  were  iirm  and  normal  in  appearance, 
but  the  greater  part  of  the  body  was  soft,  mottled  red  and  reddish - 
black,  and  was  the  seat  of  a  hemorrhagic  lesion.  No  gall-stones 
were  found  in  the  gall-bladder  or  in  the  gall-duct.  The  paren- 
chyma had  undergone  necrosis  and  the  neighboring  interstitial  tissue 
had  become  infiltrated  with  red  blood-corpuscles,  polynuclear  leuco- 
cytes, and  fibrin.  The  capillary  vessels  at  the  margin  of  the 
necrotic  area  showed  the  condition  of  hyaline  thrombosis  observed 
in  Case  II. 

In  reports  of  many  such  cases  gall-stones  are  not 
mentioned.  In  some  instances  the  lesion  has  been 
diagnosed  upon  the  operating-table  and,  no  autopsy- 
being  obtained,  the  condition  of  the  bile  passages  has 
not  been  determined.  In  a  large  proportion  of  cases 
the  autopsy  report  is  so  meagre  that  the  presence 
or  absence  of  o-all-stones  is  not  evident.  The  relative 
frequency  with  v^hich  acute  pancreatitis  is  accompanied 
by  cholelithiasis  is  difficult  to  estimate. 

In  two  of  three  cases  which  I  have  examined  gall- 
stones were  present.  A  considerable  number  of  cases 
recently  described  by  writers  who  have  reported  more 
than  one  instance,  allow  a  fairer  estimate  than  do 
reports  of  isolated  cases.  Lund,  of  Boston,  has 
reported  five  cases,"  three  of  which  were  examined  after 
death,    and    in    all    of    these    gall-stones    were    found. 


ETIOLOGY    OF   ACUTE    PANCREATITIS.  127 

Bryant  has  reported  two  cases  with  gall-stones.  Hahn 
reports  five,  upon  three  of  which  autopsy  was  per- 
formed ;  orall-stones  were  found  in  one.  Marx  has 
described  two  cases  with  gall-stones.  Of  such  recently 
reported  cases  in  which  autopsies  were  performed,  in  thir- 
teen, including  my  three,  gall-stones  were  present  in  ten. 
Pathogenesis  of  Pancreatic  He7norrhage  and  of  Hemor- 
rhagic Pancreatitis. — Histological  peculiarities  of  aciite 
hemorrhagic  pancreatitis  explain  its  relationship  to 
hemorrhage  on  the  one  hand  and  to  gangrene  on  the 
other.  Sufficient  importance  has  not  been  given  to  the 
occurrence  of  extensive  necrosis  of  the  parenchyma  and 
interstitial  tissue  as  an  essential  feature  of  the  process. 
Thus  Korte,  after  studying  forty-one  reported  cases  of 
hemorrhagic  pancreatitis,  of  which,  indeed,  few  include 
an  adequate  microscopic  description,  gives  the  following 
account  of  its  histology.  In  the  interstitial  tissue  in- 
filtration with  round  cells  accompanies  the  escape  of 
blood,  and  in  some  cases  the  interstitial  tissue  proliferates 
so  that  the  lobules  of  the  gland  are  separated  from  one 
another.  The  fat  frequently  present  in  considerable 
quantities  between  the  lobules  of  the  glandular  tissue 
contains  foci  of  necrosis.  The  acini  show  fatty  degener- 
ation, and  in  many  cases  partial  or  complete  absence  of 
nuclear  stain  indicates  the  death  of  the  cells.  Over 
a  considerable  area  glandular  tissue  may  have  under- 
gone such  change  that  epithelial  cells  are  no  longer 
recognizable. 


128  DISEASE    OF   THE    PANCREAS. 

In  two  cases  (II.  and  III.)  which  I  have  described  the 
lesion  has  been  of  short  duration  and  the  essential 
features  of  the  lesion  are  well  illustrated.  Wide- 
spread necrosis  of  the  parenchyma  is  associated  with 
abundant  hemorrhage  and  with  the  accumulation  of  in- 
flammatory products,  notably  fibrin  and  poly  nuclear 
leucocytes.  A  very  conspicuous  feature  of  the  process 
is  total  death  of  the  tissue,  implicating  at  once  epithe- 
lial cells,  interstitial  connective  tissue,  and  walls  of 
blood-vessels.  For  a  time  the  architecture  of  the 
tissue  is  preserved  and  the  outlines  of  the  acini  are 
readily  discernible,  though  the  nuclei  of  the  cells  are 
wholly  lost.  Later  the  tissue  undergoes  such  complete 
alteration  that  the  structures  composing  it  are  no  longer 
recoo^nizable.  Transition  from  such  necrotic  material 
to  living  tissue  is  abrupt,  marked  by  a  narrow  zone 
containing  fragments  of  nuclei,  polynuclear  leucocytes, 
red  blood-corpuscles,  and  fibrin.  A  character  of  the 
lesion  not  previously  noted  is  the  occurrence  of  hyaline 
capillary  thrombosis  within  the  relatively  intact  tissue 
which  lies  in  contact  with  the  necrotic  zone.  The  pres- 
ence of  numerous  polynuclear  leucocytes  and  of  fibrin 
leave  no  doubt  as  to  the  inflammatory  nature  of  the 
change,  although  bacteriological  examination  has  de- 
monstrated the  absence  of  bacterial  invasion. 

I  have  had  the  opportunity  of  examining  tissue  from 
two  additional  cases  of  acute  hemorrhagic  pancrea- 
titis obtained  from  the  Pathological  Laboratory  of  Col- 


ETIOLOGY   OF   ACUTE   PANCREATITIS.  129 

umbia  University  of  New  York,  through  the  courtesy 
of  Dr.  Hodenpyl.  In  both  cases  necrosis  of  paren- 
chyma and  interstitial  tissue  implicating  the  blood-vessels 
was  associated  with  profuse  hemorrhage  into  the  ne- 
crotic tissue.  Though  a  few  polynuclear  leucocytes 
were  present  near  the  margin  of  relatively  intact  tissue 
inflammatory  changes  did  not  form  a  conspicuous  fea- 
ture of  the  process.  Where,  as  in  Case  I.,  the  process 
is  of  longer  duration,  connective  tissue  in  contact  with 
areas  of  necrosis  undergoes  proliferation  and  newly 
formed  fibrous  tissue  tends  to  replace  parenchyma 
which  has  undergone  destruction. 

By  experimental  means  it  is  possible  to  produce  a 
lesion  of  which  the  essential  features  are  those  observed 
in  human  cases,  but  here,  the  conditions  being  under 
control,  various  stages  in  the  process  can  be  more 
readily  studied.  In  the  two  instances  (Experiments 
3  and  6)  in  which  death  followed  within  twenty-four 
hours  the  injection  of  five  cubic  centimetres  of  bile  into 
the  pancreatic  duct,  foci  of  necrosis  contained  widely-dis- 
tended blood-vessels,  while  injury  to  their  walls  was 
indicated  by  the  escape  of  numerous  red  blood-corpus- 
cles into  the  tissues  adjacent  to  them.  The  presence 
of  polynuclear  leucocytes  in  moderate  number  gave 
evidence  of  beginning  inflammation.  Proliferation  of 
the  fixed  tissue  occurs  with  rapidity,  invading  and  re- 
placing the  injured  parenchyma. 

In  both  human  and  experimental  lesions,  bile  coming 

9 


I30  '       DISEASE    OF    THE    PANCREAS. 

into  contact  with  cells  causes  their  death,  and  necrosis 
of  the  parenchyma  is  associated  with  such  injury  to  the 
adjacent  vessel  walls  that  red  blood-corpuscles  escape 
in  great  abundance.  Inflammatory  and  reparatory 
changes  are  secondary  to  death  of  tissue  and  occur  at 
the  margin  of  the  necrotic  area.  Hemorrhage  may  be 
the  result  of  necrosis  before  inflammatory  changes 
are  well  marked.  When,  as  in  the  case  described  by 
Simpson,  extensive  hemorrhage  has  followed  the  lodge- 
ment of  a  calculus  at  the  orifice  of  the  common  bile 
duct,  it  is  doubtless  due  to  necrosis  implicating  the  wall 
of  some  vessel  of  considerable  size.  Pancreatic  hem- 
orrhage and  hemorrhagic  pancreatitis  represent  a  single 
pathological  process,  and  cannot  be  sharply  defined  the 
one  from  the  other. 

Numerous  experiments  have  shown  that  a  variety  of 
substances,  including  bile,  injected  into  the  pancreas 
readily  cause  wide-spread  necrosis,  which  finds  little 
analogy  in  other  organs.  The  pancreas,  a  gland  se- 
creting substances  which  effect  the  digestion  of  proteids 
within  the  intestine,  is  after  death  capable,  like  the 
stomach,  of  causing  partial  digestion  of  its  own  sub- 
stance. It  is  not  improbable  that  the  ferments  of  the 
pancreatic  juice,  notably  trypin,  acting  upon  cells  injured 
by  contact  with  the  various  irritant  substances  which  can 
produce  hemorrhagic  pancreatitis,  have  a  part  in  the 
production  of  the  wide-spread  disintegration  of  the 
parenchyma  which  results. 


ETIOLOGY   OF   ACUTE    PANCREATITIS. 


131 


Pathogenesis  of  Gangrenous  Pancreatitis. — Though  the 
older  literature  contains  cases  in  which  the  pancreas  had 
undergone  sequestration,  an  adequate  picture  of  the 
condition  was  first  drawn  by  Fitz,  who  has  shown  that 
acute  pancreatitis  may  terminate  in  gangrene.  From  a 
study  of  fifteen  cases  Fitz  found  that  the  appearance  of 
the  pancreas  varies  with  the  duration  of  the  disease. 
The  gland,  he  says,  is  at  first  swollen,  dark  red,  and 
soft,  while  on  section  the  tissue  is  red  or  mottled  red 
and  gray,  or  may  be  wholly  transformed  into  a  dark 
slate-colored,  foul-smellino-  mass.  At  the  end  of  about 
ten  days  the  pancreas  is  often  dark-brown,  dry  and 
firm,  and  covered  by  changed  blood  ;  hemorrhagic  in- 
filtration may  extend  beyond  its  limits.  Throughout 
the  substance  areas  of  hemorrhage  alternate  with  yel- 
low spots  of  softening.  At  the  end  of  the  second 
week  the  organ  may  form  a  soft,  black,  friable  mass, 
while  the  lesser  omental  cavity  contains  a  large  quantity 
of  chocolate-colored  fluid  containing  large,  bluish-black 
clots.  The  gland  may  be  finally  transformed  into  a  soft 
mass  attached  by  a  few  shreds  to  the  posterior  abdomi- 
nal wall  or,  indeed,  may  lie  free  in  the  omental  cavity, 
which  is  distended  with  bloody  or  blackish,  often  ill- 
smelling,  fluid  containing  necrotic  particles  of  tissue.  A 
striking  feature  is  the  occurrence  of  disseminated  fat 
necrosis. 

In  reports  of  at  least  half  the  cases  studied  by  Fitz, 
hemorrhages  into  the  pancreas  were  mentioned,  or  the 


132  DISEASE    OF   THE    PANCREAS. 

discoloration  described  was  such  as  to  suggest  hem- 
orrhage. He  therefore  reached  the  conckision  that 
gangrenous  pancreatitis  and  peripancreatitis  are  in  a 
considerable  number  of  cases  associated  with  hemor- 
rhagic inflammation,  although  they  may  be  the  result 
of  perforating  inflammation  of  the  gastro-intestinal  or 
biliary  tracts.  Korte  thinks  that  necrosis  may  follow 
extensive  purulent  inflammation,  and  mentions  certain 
other  possible  causes, — for  example,  traumatism  and 
arterial  sclerosis, — but  is  of  the  opinion  that  hemorrhagic 
infiltration  usually  precedes  the  condition. 

Histological  examination  of  human  cases  and  study 
of  hemorrhagic  pancreatitis  produced  experimentally 
has  shown  that  extensive  necrosis  of  tissue  is  associated 
with  injury  to  the  blood-vessels  and  consequent  hem- 
orrhage. Sufficient  importance  has  not  been  attached 
to  the  occurrence  of  necrosis  ;  wide-spread  death  of 
tissue  is  an  essential  feature  of  hemorrhagic  pancre- 
atitis. Subsequent  alterations,  due  to  changes  occur- 
ring in  the  extravasated  blood  and  to  invasion  of  bac- 
teria, cause  such  discoloration  and  disintegration  of  the 
affected  tissue  that  it  is  recognized  by  the  naked  eye  to 
be  gangrenous.  Suppuration  with  or  without  perfora- 
tion of  the  gastro-intestinal  tract  is  a  secondary  change 
and  is  not  the  cause  of  the  gangrenous  condition.  No 
sharp  distinction,  therefore,  can  be  drawn  between 
hemorrhagic  and  so-called  gangrenous  pancreatitis. 
The  lesion  begins  with  necrosis  of  tissue,  and  hemor- 


ETIOLOGY   OF   ACUTE    PANCREATITIS.  133 

rhage  takes  place  into  the  necrotic  area  ;  inflammatory- 
changes  soon  occur,  and  should  sufficient  time  elapse, 
those  alterations  which  give  to  the  organ  the  macro- 
scopic appearance  of  gangrene  ensue. 

Gangrenous  pancreatitis  being  a  late  stage  of  the  hem- 
orrhagic inflammation,  from  the  foregoing  one  would  ex- 
pect to  find  gall-stones  frequently  associated  with  the  le- 
sion. The  table  (see  page  no)  includes  such  cases  of 
acute  pancreatitis  associated  with  cholelithiasis  ;  in  eight 
instances  the  organ  is  described  as  hemorrhagic  and  gan- 
grenous, while  in  thirteen  gangrene  alone  is  mentioned. 

Symptoms  of  Acute  Hefnorrhagic  Pancreatitis. — The 
foregoing  study  has  shown  that  no  sharp  distinction 
can  be  drawn  between  pancreatic  hemorrhage,  hemor- 
rhagic pancreatitis,  and  gangrenous  pancreatitis.  These 
processes  are  essentially  wide-spread  necrosis  of  the 
parenchyma,  associated  with  injury  to  the  blood-vessel 
walls  and  hemorrhage  ;  inflammatory  changes  rapidly 
follow,  and  so-called  gangrenous  pancreatitis  is  a  late 
stage  of  the  hemorrhagic  lesion  :  the  gland  primarily  un- 
dergoes necrosis.  While  at  present  it  cannot  be  denied 
that  other  causes  may  produce  the  condition,  only  one 
etiological  factor  has  been  demonstrated, — namely,  the 
impaction  of  a  gall-stone  in  the  diverticulum  of  Vater, 
diverting  bile  into  the  pancreatic  duct. 

An  individual,  usually  in  fairly  good  health,  with  per- 
haps a  history  of  previous  gall-stone  colic,  is  suddenly 
attacked  with    pain    in    the    epigastric    region,   accom- 


134  •        DISEASE    OF   THE    PANCREAS. 

panied  by  vomiting  and  followed  by  collapse.  Death 
follows  often  within  forty-eight  hours,  and  at  autopsy 
gall-stones  are  found  in  the  bile  passages,  while  that 
one  which  caused  the  fatal  attack  may  be  still  lodged  in 
the  common  duct  near  its  orifice.  The  pancreas  is 
enlarged,  infiltrated  with  blood,  and  hemorrhage  may 
have  occurred  into  the  surrounding  tissue.  Foci  of  fat 
necrosis  are  usually  present. 

A  fatal  termination  may  not  follow  rapidly  the  symp- 
toms mentioned.  Pain  in  the  epigastrium  persists, 
jaundice  may  be  present,  and  a  tumor-mass  above  the 
umbilicus  may  indicate  a  probable  lesion  of  the  pan- 
creas. At  the  end  of  one  or  more  weeks  or  months 
death  occurs,  often  with  symptoms  indicating  the  pres- 
ence of  suppurative  inflammation,  presumably  in  the 
neighborhood  of  the  gland.  At  autopsy  the  diagnosis 
of  cholelithiasis  is  confirmed  by  the  presence  of  gall- 
stones in  the  gall-bladder  or  in  the  bile  ducts,  and  oc- 
casionally the  offending  calculus  is  still  lodged  in  the 
diverticulum  of  Vater.  The  pancreas  is  dry,  black,  and 
necrotic,  and  evidence  of  previous  hemorrhage  may  be 
present.  Secondary  infection  has  occurred,  and  the 
pancreas  lies  in  an  abscess  cavity  formed  by  the  bursa 
omentalis.  In  the  wall,  and  often  widely  disseminated 
in  the  abdominal  fat,  are  foci  of  necrosis.  Since  the 
individual  has  survived  the  primary  lesion,  opportunity 
has  been  given  for  the  development  of  secondary 
changes  in  the  injured  pancreas  and  neighboring  fat. 


CHAPTER    VI. 

FAT    NECROSIS. 

Repeated  reference  has  been  made  to  the  occurrence 
of  necrosis  of  fat  in  association  with  acute  hemorrhagic 
pancreatitis  and  other  lesions  of  the  gland.  The  rela- 
tionship of  this  peculiar  lesion  to  alterations  of  the 
pancreas  is  now  well  established,  but  though  dissemi- 
nated focal  fat  necrosis  has  been  the  subject  of  much 
anatomical  and  experimental  research  since  Balser  di- 
rected attention  to  it  in  1882,  some  of  the  problems  it 
has  suggested  have  not  received  an  adequate  solution. 

Balser  observed  in  fat  immediately  about  the  pancreas 
small,  opaque,  white  areas,  which  were  shown  by  micro- 
scopic examination  to  be  composed  in  great  part  of 
necrotic  fat-cells.  This  lesion  was  present  in  five  of 
twenty-five  bodies  which  he  examined.  In  two  cases  a 
similar  process  not  only  implicated  the  fat  about  the 
pancreas,  but  was  present  in  scattered  foci  at  a  consid- 
erable distance  from  the  organ,  and  was,  he  believed, 
the  cause  of  death. 

When  widely  scattered  the  condition  has  been  desig- 
nated disseminated  or  multiple  fat  necrosis.  The  more 
minute  foci,  limited  to  fat  within  or  upon  the  organ, 
when  carefully  sought  for,  are  often  found  at  autopsy, 
but  their  frequency  is  somewhat  less  than  Balser  sup- 

135 


136  DISEASE   OF   THE    PANCREAS. 

posed.  Larger  foci  of  fat  necrosis  occupying  the  fat 
of  the  omentum,  the  subperitoneal  and  retroperitoneal 
tissue  are,  unlike  the  latter,  conspicuous  lesions. 

Recognition  of  this  condition,  difficult  only  on  ac- 
count of  the  relative  infrequency  with  which  it  is  en- 
countered, is  of  considerable  importance  to  the  sur- 
geon, since  it  indicates,  as  will  be  shown,  the  existence 
of  some  grave  alteration  of  the  pancreas.  On  opening 
the  abdomen  the  omentum,  and  possibly  other  fat,  is 
found  studded  with  round  or  oval  areas,  several  milli- 
metres in  diameter  and  very  conspicuous  on  account  of 
their  opaque  white,  or  yellow  color,  which  is  in  sharp 
contrast  with  the  translucent  golden  yellow  of  the  nor- 
mal fat.  A  narrow  hemorrhagic  zone  frequently  sur- 
rounds such  areas. 

This  lesion,  most  extensive  in  the  neighborhood  of  the 
pancreas,  is  usually  limited  to  the  fat  of  the  abdominal 
cavity.  Areas  of  necrosis  may  be  confluent  near  the 
gland  and  thickly  scattered  elsewhere  in  the  fat  abutting 
upon  the  peritoneal  cavity.  In  two  cases  Hansemann 
observed  foci  of  fat  necrosis  in  the  subcutaneous  tissue  ; 
they  corresponded  in  location  to  reddish  areas  visible 
during  life  upon  the  overlying  skin.  Chiari  has  recorded 
a  very  remarkable  case  :  areas  of  fat  necrosis,  often  as 
large  as  a  pea,  were  present  in  the  fatty  tissue  about  the 
bursa  omentalis  within  which  lay  the  necrotic  pancreas, 
in  the  mesentery,  in  the  subperitoneal  fat  of  the  ab- 
dominal wall,  in  the  subpericardial  and  subpleural  fat, 


FAT  NECROSIS.  1 37 

and  in  the  subcutaneous  tissue.  Balser  has  also  seen 
the  pericardial  fat  implicated  in  the  process. 

Spontaneous  fat  necrosis  has  been  found  in  domestic 
animals  by  several  observers, — Balser,  Williams,  Olt, 
and  others.  In  pigs  very  wide-spread  dissemination  of 
the  lesion  has  been  found  by  Olt,  who  records  its  pres- 
ence in  the  subperitoneal  fat,  in  the  intermuscular  septa, 
and  in  the  subcutaneous  tissue  of  the  abdominal  and 
thoracic  walls. 

Fitz  first  has  offered  the  suggestion  that  fat  necrosis  is 
consequent  upon  a  lesion  of  the  pancreas,  and  has  sup- 
ported this  conclusion  by  numerous  instances  in  which 
the  two  conditions  have  been  associated.  In  the  majority 
of  cases  hemorrhagic  pancreatitis  is  present,  and  not 
infrequently  the  organ  is  found  to  be  gangrenous  in 
appearance.  Occasionally  the  gland  lies  in  the  cavity 
of  the  bursa  omentalis  dissected  almost  free  from  the 
surrounding  tissue ;  such  sequestration,  Langerhans 
thinks,  may  be  the  result  of  extensive  necrosis  of  the 
fat  surrounding  it.  More  rarely  other  pathological 
conditions  are  present ;  chronic  suppurative  pancreatitis 
is  rarely  accompanied  by  fat  necrosis,  and  in  a  few 
instances  chronic  interstitial  inflammation  has  co-existed 
with  it. 

The  chemical  and  histological  studies  of  Langerhans 
have  explained  the  essential  nature  of  the  process. 
He  has  shown  that  the  changes  demonstrable  within 
the  fat-cells  are  associated  with  the  splitting  of  the  fat- 


138  DISEASE    OF   THE   PANCREAS. 

molecule  into  its  fatty  acid  and  the  soluble  constituent 
glycerin.  Fatty  acids  are  deposited  as  needle-like 
crystals  within  the  cell  which  has  lost  its  nucleus  and  is 
evidently  necrotic,  while  the  soluble  glycerin  is  ab- 
sorbed. Very  soon  the  fatty  acids  unite  with  calcium 
to  form  calcium  salts,  and  within  the  cell  outline  which 
is  still  preserved  are  irregular,  often  globular  masses, 
in  which  the  presence  of  lime  salts  may  be  demon- 
strated by  microchemical  reactions.  A  proliferation  of 
fixed  tissue-cells  occurs  at  the  periphery  of  the  necrotic 
area,  and  is  most  conspicuous  in  the  neighborhood  of 
strands  of  connective  tissue,  but  often  the  zone  of  re- 
action is  not  complete,  and  necrotic  cells  are  in  contact 
with  those  which  are  still  unchanged. 

A  few  polynuclear  leucocytes  find  their  way  to  the 
periphery  of  the  necrotic  tissue,  but  when  numerous 
their  presence  is  the  result  of  secondary  infection  of 
the  dead  tissue.  In  the  peripheral  zone  of  cell  pro- 
liferation, in  addition  to  cells  of  lymphoid  type,  are  much 
larger  round  or  oval  cells  with  vesicular  nuclei  and 
abundant  cytoplasm  studded  with  minute  fat-globules, 
doubtless  fat-cells  in  process  of  multiplication.  Similar 
cells  are  occasionally  multinucleated  and  of  such  size 
that  they  may  be  called  giant  cells. 

Etiology. — Attempts  have  been  made  to  refer  the 
occurrence  of  fat  necrosis  to  the  action  of  micro-organ- 
isms, and  in  many  cases  bacteria  have  been  isolated  from 
the  lesion.     The  explanation  of  their  presence  is  doubt- 


FAT   NECROSIS. 


139 


less  that  proposed  by  Dr.  Welch,  who  identified  the 
bacillus  coli  in  a  case  of  hemorrhagic  pancreatitis  with 
fat  necrosis.  Diphtheritic  and  ulcerative  colitis  was 
present,  and  the  colon  bacillus  was  found  not  only  in 
foci  of  fat  necrosis,  but  in  the  mesenteric  glands,  the 
liver,  the  bile,  the  lungs,  the  spleen,  and  the  kindeys. 
The  lesion  of  the  colon  had  apparently  facilitated  the 
invasion  of  the  bacillus  coli,  and  its  presence  in  foci  of 
fat  necrosis  was  thought  to  be  a  secondary  event  having 
no  relation  to  their  production.  Similar  conclusions 
have  been  reached  by  a  number  of  observers,  Hlava, 
Fitz,  Leonhard,  and  others,  who,  cited  in  a  preceding 
chapter,  have  isolated  a  considerable  variety  of  bacteria 
from  cases  of  fat  necrosis  accompanying  hemorrhagic 
pancreatitis.  The  discordant  results  of  bacteriological 
examinations  give  little  support  to  the  opinion  of  a  few 
observers  who  have  suggested  that  the  lesion  is  caused 
by  micro-organisms. 

The  proximity  of  foci  of  fat  necrosis  to  the  pancreas 
and  their  association  with  various  pancreatic  lesions  has 
suggested  the  possibility  that  products  of  the  organ 
are  active  in  their  causation.  To  test  this  hypothesis, 
Langerhans  injected  into  the  fat-tissue  of  rabbits  and 
dogs  an  infusion  prepared  with  antiseptic  precautions 
from  the  pancreas  of  rabbits,  and  in  one  of  thirteen 
experiments  succeeded  in  producing  in  the  perirenal  fat 
of  a  dog  a  small  opaque  focus  which  had  the  histologi- 
cal characteristics  of  fat  necrosis,  but  was  accompanied 


I40  DISEASE    OF   THE   PANCREAS. 

by  an  acute  inflammatory  reaction.  He  reached  the 
conclusion  that  pancreatic  juice  acting  on  living  fat- 
tissue  causes  necrosis.  Jung  attempted  to  reproduce 
the  condition  experimentally  by  introducing  pieces  of 
the  fresh  pancreatic  tissue  of  one  animal  into  the  ab- 
dominal cavity  of  another,  and  in  one  of  four  experi- 
ments succeeded  in  producing  well-marked  areas  of 
necrosis.  In  the  remaining  instances  peritonitis  resulted 
and  his  success  was  doubtful. 

The  experiments  of  Hildebrand  and  Dettmer  are 
interesting  and  important.  By  placing  a  ligature  about 
the  pancreas  they  obtained  necroses  in  the  fat  about 
that  part  of  the  gland  distal  to  the  ligature.  In 
other  experiments  they  tied  the  veins  of  the  ligatured 
part  to  prevent,  as  Hildebrand  suggests,  the  pos- 
sible absorption  of  the  obstructed  secretion.  The 
gland-tissue  became  congested  and  infiltrated  with 
blood,  and  in  its  neighborhood  foci  of  fat  necrosis  were 
somewhat  more  abundant  than  in  the  former  instances. 
They  were  able,  moreover,  to  produce  similar  lesions  in 
the  immediate  neighborhood  of  the  gland  by  merely 
cutting  the  organ  transversely,  thus  allowing  the  pan- 
creatic juice  free  access  to  the  abdominal  cavity.  Hil- 
debrand comes  to  the  conclusion  that  obstruction  to  the 
outflow  of  the  secretion,  alone  or  combined  with  occlu- 
sion of  the  veins,  or  the  escape  of  pancreatic  juice  into 
the  peritoneal  cavity  results  in  the  production  of  typical 
fat  necrosis  about  the  pancreas  and  even  in  the  omentum 


FAT   NECROSIS.  141 

and  in  the  mesentery.  Both  Flexner  and  Williams 
have  confirmed  the  observations  of  Hildebrand  and 
Dettmer.  By  placing  a  ligature  about  the  gland,  tying 
the  veins  of  the  part  of  the  organ  distal  to  the  ligature, 
and  at  times  tearing  the  parenchyma  with  a  sharp  hook, 
they  obtained  fat  necrosis  in  a  considerable  number  of 
their  experiments. 

Milisch  attempted  to  reproduce  the  lesion  in  cats  by 
allowing  the  pancreatic  juice  to  escape  into  the  peri- 
toneal cavity.  A  section,  several  centimetres  in  length, 
was  excised  from  the  splenic  arm  of  the  gland  near  the 
duodenum,  thus  isolating  the  remainder  of  the  splenic 
part  and  giving  its  secretion  free  access  to  the  abdom- 
inal cavity.  A  ligature  was  applied  about  the  duodenal 
part  of  the  cut  organ  to  prevent  the  penetration  of  in- 
fectious material  along  the  severed  duct  from  the  duo- 
denum. In  two  animals  so  operated  upon  no  fat  ne- 
crosis resulted  at  the  end  of  fifteen  and  of  six  days  ;  in 
one  of  these  experiments  a  small  concretion  was  found 
near  the  orifice  of  the  severed  duct,  while  in  the  other, 
Milisch  states,  the  duct  was  found  to  have  been  included 
in  a  ligature  placed  about  a  bleeding  vessel,  thus  pre- 
venting the  escape  of  the  secretion  into  the  cavity.  In 
three  experiments,  in  which  the  excised  piece  of  pan- 
creas was  left  free  in  the  peritoneal  cavity,  necroses 
were  found  in  the  immediate  neighborhood  of  the 
organ  and  about  the  transplanted  tissue.  He  con- 
cludes from  his  experiments,  which  are  not  convincing, 


142 


DISEASE    OF   THE    PANCREAS. 


that  fat  necrosis    may  be   caused  by  pancreatic  juice 
which  has  escaped  into  the  abdominal  cavity. 

Oser  produced  foci  of  necrosis  about  the  pancreas 
and  in  the  omentum  by  Hgating  all  the  blood-vessels  of 
the  organ  and  separating  it  from  the  duodenum,  thus 
depriving  it  of  its  blood  supply.  By  completely  ob- 
structing the  circulation  of  part  of  the  pancreas  for 
twenty  minutes,  Blume  produced  hemorrhagic  infiltra- 
tion of  the  tissue  and  fat  necrosis  in  the  neighborhood  of 
the  injured  parenchyma.  In  a  large  number  of  experi- 
ments Katz  and  Winkler  succeeded  in  producing  fat 
necrosis  by  placing  a  variable  number  of  ligatures,  at 
times  as  many  as  ten,  about  the  gland.  They  came  to 
the  conclusion  that  though  the  efficient  factor  in  the 
production  of  necrosis  is  the  fat-splitting  ferment  of  the 
pancreas,  its  activity  is  developed  in  those  situations 
where  resistance  is  lowered  by  infiltration  with  blood  or 
by  obstruction  to  the  circulation,  conditions  produced 
by  their  method  of  experimentation. 

A  number  of  experimenters — Hlava,  Korte,  Oser, 
and  recently,  as  already  mentioned,  Flexner  —  have 
obtained  necrosis  of  fat  by  injecting  into  the  paren- 
chyma of  the  gland,  or  into  the  duct  after  opening  the 
duodenum,  various  substances, — artificial  gastric  juice, 
dilute  acids  and  alkalies,  turpentine,  and  suspensions 
of  a  variety  of  bacteria, — causing  thereby  an  injury 
to  the  orland-substance  and  in  most  instances  hemor- 
rhagic  inflammation. 


FAT   NECROSIS. 


143 


In  the  experiments  cited  above  conditions  have  been 
present  which  afford  an  opportunity  for  the  escape  of 
the  pancreatic  secretion  into  the  tissue  surrounding  the 
gland  ;  it  may  be  forced  backward  into  the  tissue  as  a 
result  of  duct-obstruction,  or,  when  the  parenchyma  is 
injured,  gradual  diffusion  may  take  place.  Ever  since 
Langerhans  explained  the  process  which  takes  place 
within  the  fat-cell,  it  has  been  assumed  that  the  fat- 
splitting  ferment  of  the  pancreas  is  the  active  factor  in 
producing  the  lesion.  Demonstration  of  a  fat-splitting 
ferment  in  the  necrotic  foci  was  made  by  Flexner.  Bits 
of  altered  tissue  from  human  and  from  experimental 
cases,  when  brougfht  into  contact  with  neutral  butter- 
fat,  were  found  to  contain  a  ferment  which  has  the 
power  of  splitting  the  fat  and  setting  free  acids  readily 
recognized  by  their  odor  and  reaction. 

Fat  necrosis  produced  by  experimental  methods  has 
been  limited  to  the  abdominal  fat,  and  usually  to  the 
immediate  neighborhood  of  the  pancreas.  The  wide 
distribution  occasionally  observed  in  human  cases, 
where  almost  the  entire  abdominal  fat  may  be  studded 
with  necrotic  foci,  is  not  reproduced. 

It  is  difficult  to  believe  that  alterations  so  widely 
disseminated  and  at  so  great  a  distance  from  the  pan- 
creas are  caused  by  contact  with  its  secretion,  and  it 
has  been  suggested  that  the  process  is  not  in  all 
cases  the  same.  Oser,  in  his  work  upon  diseases 
of  the  pancreas,  summarizes  the  result  of  experimental 


144  DISEASE   OF   THE   PANCREAS. 

observations :  though  the  experiments  of  Hildebrand, 
Dettmer,  Jung,  and  others  indicate  that  aherations  in 
the  pancreas  and  in  the  surrounding  fat  are  due  to  con- 
tact with  the  pancreatic  secretion,  this  hypothesis  will 
not  explain  the  widely  disseminated  focal  necroses  ob- 
served not  only  in  distant  parts  of  the  abdominal 
cavity  but  even  in  the  subcutaneous  and  subpericardial 
fat. 

Experimental  Fat  Necrosis. — In  experiments  which  I 
have  undertaken  ^  it  has  been  found  possible  to  produce 
focal  necrosis  of  the  fat-tissue  as  wide-spread  as  that 
observed  in  human  cases  and  in  lower  animals.  They 
show  that  complete  obstruction  to  the  outflow  of  the 
pancreatic  secretion  may  cause,  after  the  lapse  of  sev- 
eral weeks,  necrosis  of  the  fat  in  parts  far  distant  from 
the  pancreas. 

Both  pancreatic  ducts  were  ligated  in  two  places  and 
cut  between  the  ligatures.  In  the  cat,  which  was 
used  for  these  experiments,  the  main  duct  enters  the 
duodenum  with  the  common  bile  duct  and  is  readily 
found.  By  carefully  separating  the  pancreas  from  the 
duodenum  the  smaller  duct  may  be  exposed,  pene- 
trating the  intestine  about  one  centimetre  below  and 
somewhat  to  the  left  of  the  larger.     The  operation  ne- 

^  Contributions  to  the  Science  of  Medicine,  dedicated  to  William 
H.  Welch,  Johns  Hopkins  Hospital  Reports,  1900,  ix.  859.  The 
experiments  to  be  quoted  are  designated  by  the  numbers  used  in  this 
article. 


FAT   NECROSIS.  145 

cessitates  little  or  no  injury  to  the  substance  of  the 
gland.  In  several  instances,  in  order  to  facilitate  the 
penetration  of  the  secretion  into  the  fat-tissue,  the  right 
border  of  the  omentum  near  its  gastric  attachment  was 
drawn  through  the  opening  made  by  separating  the 
pancreas  from  the  duodenum.  The  more  successful 
experiments  will  be  described  in  detail. 

Experiment  I. — A  full-grown  cat,  of  which  the  pancreatic  ducts 
were  ligated,  died  at  the  end  of  twenty-five  days.  The  subcutaneous 
fat  over  the  lower  half  of  the  abdomen  and  in  front  of  the  symphysis 
pubis  is  profusely  studded  with  conspicuous  opaque,  white  foci  of 
irregular  shape,  often  two  millimetres  in  diameter.  On  opening  the 
abdominal  cavity,  which  contains  a  small  quantity  of  turbid,  yellowish- 
white  fluid,  the  omentum  presents  itself  as  an  almost  homogeneous 
mass  of  opaque,  white,  slightly  friable  material.  Its  right  border  is 
adherent  over  that  part  of  the  pancreas  which  was  separated  from  the 
duodenum  at  the  time  of  operation,  and  therefore  covers  the  distal 
ends  of  the  ligated  ducts.  The  fat  of  the  mesentery  of  both  the 
small  and  large  intestines  is  converted  into  the  same  opaque,  white 
material  and  the  perirenal  fat,  the  retroperitoneal  fat,  and  masses  in 
the  pelvis  on  either  side  of  the  bladder  show  in  large  part  the  same 
transformation.  Below  the  peritoneum  of  the  diaphragm  and  of 
the  lateral  abdominal  walls  are  numerous  slightly  raised  areas  of 
similar  appearance.  The  pericardial  cavity  contains  no  excess  of 
fluid.  The  greater  part  of  the  fat  in  the  parietal  layer  of  the 
pericardium  is  of  normal  translucent  appearance,  but  on  the  right 
side  are  several  conspicuous  areas  of  opaque,  white  color,  irregular 
in  shape  and  about  two  millimetres  across.  Along  the  carotid  and 
left  subclavian  arteries  are  several  similar  foci.  The  pancreas,  of 
which  the  duodenal  part  is  embedded  in  a  homogeneous  mass  of 


146 


DISEASE    OF   THE    PANCREAS. 


transformed  fat,  is  fairly  soft  in  consistence,  though  apparently 
much  smaller  than  usual.  A  culture  on  agar-agar  from  the  perito- 
neal exudate  remained  sterile.  Microscopic  examination  of  stained 
sections  made  from  the  opaque,  white  fat  of  the  omentum,  subcu- 
taneous tissue,  and  pericardium  demonstrates  the  histological  char- 
acteristics of  fat  necrosis.  The  omentum  is  not  wholly  transformed, 
as  it  appears  to  be  upon  macroscopic  examination,  but  about  its 
blood-vessels  is  intact  tissue.  Between  the  necrotic  material  and  the 
unchanged  fat  is  usually  seen  a  well-marked  zone  of  cell-prolifer- 
ation. The  pancreas  shows  a  moderate  increase  of  its  interstitial 
tissue. 

Experiment  II. — The  pancreatic  ducts  of  a  full-grown  cat  were 
ligated  in  two  places  and  cut  between  the  ligatures.  In  exposing  the 
ducts  the  pancreas  was  separated  from  the  duodenum  for  a  distance 
of  about  four  centimetres.  The  right  margin  of  the  omentum  was 
drawn  through  the  opening  thus  made  and  fixed  by  several  silk 
sutures  over  the  distal  ends  of  the  severed  ducts.  The  animal  died 
twenty  days  after  the  operation.  On  dissecting  back  the  skin  from 
the  abdomen  and  flanks  the  subcutaneous  tissue  is  found  to  contain 
conspicuous  opaque,  white  areas,  the  largest  of  which  are  about  two 
millimetres  in  diameter.  The  fat  in  front  of  the  symphysis  pubis 
is  studded  with  minute  areas  of  similar  appearance.  The  peri- 
toneal cavity  contains  turbid  fluid.  The  omentum  is  transformed 
into  an  almost  homogeneous  mass  of  opaque,  white  material,  which  is 
somewhat  friable  in  consistence.  The  mesenteric  fat  of  the  small 
and  large  intestines  is  very  thickly  studded  with  large,  conspicuous, 
opaque,  white  areas.  The  retroperitoneal  fat  is  in  large  part  opaque 
and  white,  and  upon  the  surface  of  the  diaphragm  are  numerous 
foci  of  similar  character.  In  the  parietal  layer  of  the  pericardium 
are  several  very  conspicuous  areas  of  fat  necrosis.  The  pancreas  is 
of  small  size  and  firmer  than  usual. 

Stained  coverslip  preparations  made  from  the  peritoneal  exudate 


FAT   NECROSIS. 


147 


contain  numerous  desquamated  endothelial  cells,  but  leucocytes  are 
almost  completely  absent,  and  bacteria  are  not  discoverable.  A 
small  piece  of  omentum  and  a  bit  of  subcutaneous  fat  containing 
opaque  foci  were  tested  for  the  presence  of  a  fat-splitting  ferment, 
and  well-marked  reactions  were  obtained. 

In  these  experiments  necrosis  involving  almost  the 
entire  omental  fat,  the  greater  part  of  that  of  the  mes- 
entery, and  to  less  extent  the  fat-tissue  below  the 
parietal  peritoneum  of  the  perirenal  region,  the  lateral 
abdominal  walls,  and  the  diaphragm,  the  fat  of  the  sub- 
cutaneous tissue  and  of  the  pericardium  has  followed 
the  ligation  of  both  pancreatic  ducts.  Obstruction  to 
the  outflow  of  the  pancreatic  secretion  causes  its  diffu- 
sion into  the  surrounding  tissue.  Although  no  colored 
constituent,  like  the  pigment  of  the  bile,  makes  the 
pancreatic  secretion  evident  to  the  eye,  its  presence 
is  shown  by  the  injurious  effects  which  it  has  upon  the 
tissues.  Jaundice  is  the  index  of  hepatic  obstruction, 
while  fat  necrosis  indicates  obstruction  of  the  pancre- 
atic ducts.  In  accordance  with  this  relationship  to  the 
pancreas,  we  find  that  changes  in  the  fat-tissue  are 
most  marked  in  the  neighborhood  of  the  organ,  while 
in  more  distant  parts,  which  may  be  reached  by  gradual 
diffusion  through  continuous  layers  of  connective  tissue, 
the  process  is  much  less  extensive. 

A  fat-splitting  ferment,  presumably  that  of  the  pan- 
creatic juice,  has  been  shown  by  the  method  practised 
by  Flexner   to   be   present  in  the  distant   foci  of  the 


148  DISEASE    OF   THE    PANCREAS. 

subcutaneous    tissue,    as    well    as    in    the    necrotic    fat 
adjacent  to  the  pancreas. 

In  the  first  experiment  the  animal  died  at  the  end  of 
twenty-five  days  ;  in  the  second,  in  which  the  lesion  was 
somewhat  less  extensive,  in  twenty  days.  In  four  sub- 
sequent experiments  the  animal  survived  a  shorter 
time,  and  presumably  less  opportunit}''  was  afforded  for 
the  diffusion  of  the  secretion.  The  distribution  of 
necrosis  was  much  less  extensive  and  was  confined  to 
the  fat  in  close  proximity  to  the  pancreas. 

Disseminated  necrosis  does  not  constantly  follow  liga- 
tion of  the  pancreatic  ducts,  and  in  three  experiments 
foci  of  necrosis  were  not  demonstrable  after  death. 
One  of  these  animals  survived  the  operation  only 
twenty-four  hours,  and  the  minute  yellowish-white 
areas  which  were  seen  about  the  site  of  operation  and 
in  the  omentum  near  by,  proved  on  microscopical  ex- 
amination to  be  small  collections  of  leucocytes,  which 
elsewhere  were  diffusely  scattered  through  the  tissue, 
In  another  experiment,  in  which  the  ducts  were  ligated 
and  cut  and  the  mesentery  fixed  over  their  distal  ends, 
no  necroses  were  found  at  the  end  of  two  days.  A 
third  cat,  of  which  the  ducts  were  ligated  but  not  cov- 
ered by  the  omentum,  survived  twenty-five  days,  and 
no  foci  of  fat  necrosis  were  found  at  autopsy  ;  the  pan- 
creas was  diminished  in  size  and  firm  in  consistence 
and  the  main  duct  was  markedly  dilated.  Microscopic 
examination   demonstrated  the   presence   of  advanced 


FAT   NECROSIS.  149 

chronic  interstitial  inflammation.  It  is  possible  that 
induration  of  the  interstitial  tissue  consequent  upon 
chronic  inflammation  may  retard  the  diflusion  of  the 
obstructed  secretion. 

In  the  experiments,  in  which  widely  disseminated 
necrosis  followed  ligation  of  the  ducts,  the  animal  sur- 
vived, one,  twenty,  the  other,  twenty-five  days  ;  while 
in  several  instances,  in  which  the  animal  lived  a  shorter 
time,  less  extensive  necrosis  resulted.  These  facts  may 
be  explained  by  assuming  a  gradual  diffusion  of  the 
pancreatic  secretion.  If  such  be  the  case,  stimulation 
of  the  secreting  activity  of  the  gland  after  ligation  of 
its  ducts  will  hasten  the  diffusion  and  more  rapidly 
cause  necrosis  in  parts  distant  from  the  organ.  In 
order  to  test  this  hypothesis,  pilocarpin,  which  has  been 
shown  by  Heidenhain,  Gottlieb,  and  others  to  stimulate 
pancreatic  secretion,  was  administered  to  an  animal  of 
which  the  ducts  had  been  ligated. 

Experiment  X. — The  pancreatic  ducts  of  a  full-grown  cat  were 
isolated,  and  each  was  bound  by  a  single  silk  ligature  ;  the  ducts  were 
not  cut.  Pilocarpin  muriate  (0.005  gramme)  was  injected  subcuta- 
neously  on  the  following  day  at  12  m.,  and  again  at  2  p.m.;  two 
days  later  the  same  dose  was  repeated  at  2  p.m.  On  the  follow- 
ing day,  at  11  a.m.,  the  animal  was  found  dead.  The  omentum  is 
studded  throughout  with  conspicuous  opaque,  white  areas ;  along  the 
right  border  near  the  stomach  they  are  confluent,  and  involve  almost 
the  whole  surface  (see  Fig.  13).  Similar  areas  are  thickly  scattered 
in  the  duodenal  mesentery  near  the  pancreas,  and  in  the  mesentery 
of  the  small  and  large  intestine.     The  retroperitoneal   tissue,  par- 


ISO 


DISEASE    OF   THE    PANCREAS. 


ticularly  on  the  right  side,  presents  large  superficial  areas  of  the  same 
character,  while  in  the  subperitoneal  tissue  upon  the  surface  of  the 
diaphragm  and  in  the  intermuscular  septa  of  the  abdominal  wall 
opaque  areas  are  conspicuous.  In  the  anterior  and  right  wall  of  the 
parietal  pericardium  are  scattered  opaque,  white  foci  about  two  milli- 
metres in  diameter.     The  pancreas  is  firm  in  consistence. 

Control. — The  operation  performed  upon  the  preceding  animal 
was  repeated  on  a  well-grown  cat,  which  was  killed  at  the  end  of 
four  days ;  pilocarpin  was  not  administered.  Minute  opaque,  white 
areas  are  present  in  the  neighborhood  of  the  ligated  ducts,  in  the 
omentum  near  the  pyloric  end  of  the  stomach,  and  in  the  mes- 
entery, but  are  confined  to  the  immediate  neighborhood  of  the 
pancreas. 

When  the  ducts  of  the  pancreas  are  ligated  and  cut, 
two  possible  methods  by  which  its  secretion  may  pene- 
trate into  the  surrounding  adipose  tissue  suggest  them- 
selves :  {a)  dammed  back  upon  the  gland,  when  the 
pressure  within  the  duct  has  reached  a  certain  height, 
the  secretion  may  be  forced  through  the  substance  of 
the  organ  into  the  tissues  about ;  and  [b)  should  the 
duct  rupture  at  the  point  where  the  ligature  is  applied, 
it  may  be  poured  directly  into  the  neighboring  tissue. 
In  several  of  the  experiments  cited  above,  the  ligatures 
applied  to  the  distal  cut  ends  were  found  surrounded  by 
necrotic  fat,  lying  in  softened  material,  from  which  they 
were  readily  removed.  The  distribution  of  the  lesion, 
which  is  most  intense  in  the  peripancreatic  tissue  and 
in  the  neighboring  omentum  and  mesentery,  indicates 
that  fat  necrosis  is  not  caused  by  pancreatic  secretion 


Fig.  13. — Experimental  fat  necrosis :  administration  of  pilocarpin  after  ligation  of  the  pan- 
creatic ducts.  Foci  of  necrosis  in  the  omental  and  mesenteric  fat,  in  fat  below  the  parietal 
peritoneum  and  in  fat  of  the  parietal  pericardium  1  Experiment  X. ). 


FAT    NECROSIS.  151 

poured  directly  into  the  peritoneal  cavity.  If  such  were 
the  case,  we  would  expect  a  more  generalized  dissemi- 
nation of  the  foci.  Similar  objections  are  applicable  to 
the  conclusions  of  Milisch,  previously  referred  to. 

In  order  to  test  the  ability  of  the  fully-formed  pan- 
creatic juice  to  produce  fat  necrosis  when  injected  into 
fat-tissue,  an  attempt  was  made  to  cause  the  secretion 
to  escape  directly  from  the  gland  into  the  subcutaneous 
fat.  To  accomplish  this  object  the  following  operation 
was  performed  :  An  incision  was  made  through  the  ab- 
dominal wall  in  the  median  line  below  the  sternum. 
Over  a  small  area  to  the  left  of  the  incision  the  skin 
and  subcutaneous  fat  were  dissected  from  the  under- 
lying rectus  muscle  ;  through  the  muscle  was  made  a 
short  opening  parallel  to  the  median  line  and  about 
one  and  a  half  centimetres  from  it.  The  pancreatic 
ducts  were  ligated  in  two  places  and  cut  between  the 
ligatures,  and  the  pancreas  was  dissected  free  from  the 
duodenum.  It  was  now  possible  to  bring  the  duodenal 
part  of  the  pancreas  bearing  the  distal  ends  of  the  sev- 
ered ducts  through  the  opening  in  the  rectus  muscle. 
A  few  silk  sutures  between  the  muscle  and  gland  re- 
tained the  latter  in  such  position  that  the  subcutaneous 
fat  covered  the  ends  of  the  ducts.  The  abdominal 
wound  in  the  median  line  was  closed  and  the  ligatured 
ends  of  the  ducts  now  lay  in  contact  with  the  subcuta- 
neous fat.  The  previous  experiments  have  shown  that 
in  many  instances  the  ligature  in  time  ceases  to  bind 


152  DISEASE    OF    THE   PANCREAS. 

the  duct,  and  is  found  loose  in  the  tissue  ;  but  before  this 
had  taken  place  opportunity  was  afforded  for  the  partial 
healing  of  the  abdominal  wound,  so  that  the  secretion, 
finally  escaping,  was  poured  into  the  subcutaneous  fat. 
The  operation  was  performed  upon  three  animals. 
In  two  instances  suppuration  of  the  abdominal  wound 
ensued  and  no  necrosis  of  fat  resulted. 

Experiment  XIII. — The  operation  previously  described  was  per- 
formed upon  a  full-grown  cat.  The  animal,  which  became  much 
emaciated,  died  twenty-seven  days  later.  Opposite  the  transplanted 
pancreas  is  a  cavity  in  the  subcutaneous  tissue  undermining  the  skin 
for  a  considerable  distance  to  the  left  of  the  median  line  and  con- 
taining thick,  viscid  material,  which  microscopically  shows  fat-glob- 
ules in  abundance,  but  no  leucocytes.  The  cavity  has  broken 
through  the  skin  at  a  point  opposite  the  pancreas.  The  tissue 
forming  its  wall  is  very  thickly  studded  with  irregular,  opaque,  white 
areas,  which  in  many  places  are  confluent,  forming  masses  of  homo- 
geneously necrotic  fat.  Foci  of  fat  necrosis  are  widely  scattered  in 
the  subcutaneous  tissue  on  the  left  side  over  the  thorax  and  over  the 
abdominal  wall,  where  they  are  most  abundant  opposite  the  above- 
mentioned  cavity.  The  pancreas  is  diminished  in  size  and  firm  in 
consistence. 

A  section  for  microscopic  examination  was  made  through  the 
wall  of  the  cavity  in  the  subcutaneous  tissue.  Here  and  there  are 
groups  of  necrotic  fat-cells,  representing  usually  an  entire  lobule. 
The  outlines  of  the  cells  are  for  the  most  part  well  preserved,  and 
about  the  foci  of  necrosis  is  a  zone  of  newly-formed  cells  closely 
packed  together.  Sections  of  the  subcutaneous  tissue,  at  a  consid- 
erable distance  from  the  cavity,  contain  similar  areas  of  fat 
necrosis. 


FAT   NECROSIS.  153 

The  foregoing  experiments  show  that,  by  causing  the 
entire  pancreatic  secretion  of  the  cat  to  penetrate  into 
the  tissue  about  the  pancreas,  wide-spread  necrosis  of 
the  fat,  not  only  of  the  abdomen,  but  of  the  subcuta- 
neous tissue  and  of  the  pericardium  as  well,  may  result, 
thus  reproducing  the  wide-spread  dissemination  ob- 
served in  man.  The  extent  of  the  process  is  depend- 
ent upon  the  gradual  diffusion  of  the  fat-splitting  fer- 
ment, and  corresponds  in  some  degree  with  the  length 
of  time  which  the  animal  has  survived  the  operation  ; 
stimulation  of  the  secreting  activity  of  the  gland  hastens 
this  diffusion. 

By  the  methods  of  experimentation  employed,  but 
little  injury  is  done  to  the  substance  of  the  gland  and 
no  disturbance  of  its  circulation  results.  Hildebrand 
has  suggested  that  obstruction  to  the  venous  circula- 
tion, preventing  the  absorption  by  the  blood  of  pan- 
creatic secretion  which  has  found  its  way  into  the 
tissues,  may  favor  the  production  of  fat  necrosis.  The 
wide-spread  necrosis  produced  by  mere  ligation  of  the 
ducts  indicates  that  disturbances  of  the  circulation  play 
but  little  part  in  the  process.  It  is,  however,  by  no 
means  improbable  that  pancreatic  ferments  free  in  the 
tissue  are  in  part  absorbed  and,  it  may  be,  destroyed. 
Katz  and  Winkler,  as  already  mentioned,  conclude  from 
their  experiments  that  hemorrhagic  infiltration  or  local 
ischsemia,  by  lowering  the  resistance  of  the  tissue,  are 
factors  in  the  production  of  focal  necroses.     The  ab- 


154  DISEASE    OF   THE   PANCREAS. 

sence  of  these  conditions  in  the  preceding  experiments 
shows  that  they  are  at  least  not  essential. 

It  is  well  known  that  chronic  interstitial  pancreatitis 
is  produced  by  occlusion  of  the  pancreatic  duct ;  and  in 
those  instances  in  which  the  animal  survived  the  opera- 
tion four  or  five  days  this  change  was  evident.  That  it 
is  not  a  factor  essential  to  the  production  of  fat  necrosis 
is  shown  by  its  absence  in  one  experiment  in  which, 
though  the  animal  lived  but  twenty-four  hours  after 
ligation  of  the  ducts,  numerous  small  foci  of  necrosis 
were  present.  It  was  not  observed,  moreover,  at  the 
end  of  four  days  after  ligating  the  ducts  and  injecting 
pilocarpin,  though,  as  already  described,  very  widely  dis- 
seminated focal  necrosis  resulted.  In  one  before  men- 
tioned experiment  the  animal  died  twenty-five  days 
after  ligation  of  the  ducts,  and,  though  advanced 
chronic  interstitial  inflammation  resulted,  fat  necrosis 
was  absent.  Indeed,  it  is  not  improbable  that  chronic 
inflammatory  changes  following  duct-obstruction  tend 
to  limit  dissemination  of  fat  necrosis  by  retarding  diffu- 
sion of  the  pancreatic  ferments. 

Application  of  Experimental  Observations. — Condi- 
tions resembling  in  greater  or  less  degree  those  of 
the  foregoing  experiments  are  at  times  associated 
with  focal  fat  necrosis  in  human  subjects.  Obstruc- 
tion of  the  duct  of  Wirsung  has  in  a  number  of  cases 
been  accompanied  by  necrosis  of  fat,  though,  as  a 
rule,  lesions  of  the  parenchyma  secondary  to  duct  ob- 


FAT   NECROSIS.  155 

struction  have  also  been  present.  Dieckhoff  records 
such  a  case  in  which  the  widened  duct  was  filled  with 
concretions  and  the  gland  was  the  seat  of  purulent  in- 
flammation. In  an  autopsy  performed  by  Dr.  Welch 
in  the  pathological  laboratory  of  the  Johns  Hopkins 
Hospital  small  foci  of  peripancreatic  fat  necrosis  were 
associated  with  occlusion  of  the  pancreatic  duct  by 
numerous  calculi ;  the  gland  was  the  seat  of  chronic 
inflammation.  Williams  records  a  similar  case.  Car- 
cinoma of  the  head  of  the  pancreas  occluding  the  com- 
mon bile  duct — and  presumably  the  duct  of  Wirsung 
as  well — was  in  a  case  of  Katz  and  Winkler  accom- 
panied by  focal  fat  necrosis. 

Dieckhoff  describes  a  case  of  cholelithiasis  in  which 
a  gall-stone  was  found  lodged  in  the  duct  of  Wirsung  ; 
and  about  the  pancreas,  which  microscopic  examination 
showed  to  be  the  seat  of  purulent  inflammation,  were 
foci  of  fat  necrosis.  In  several  instances  gall-stones 
have  been  found  lodged  in  the  ampulla  of  Vater,  par- 
tially or  completely  closing  the  main  pancreatic  duct ; 
and  though  the  size  of  the  stone  or  anatomical  pecu- 
liarities of  the  diverticulum  have  prevented  the  occur- 
rence of  hemorrhagic  pancreatitis,  foci  of  fat  necrosis 
have  been  produced.  Of  especial  interest  are  the  cases 
reported  by  Flexner  and  by  Fraenkel,  in  which,  though 
disseminated  fat  necrosis  was  present,  no  lesion  of  the 
pancreas  was  recorded.  In  the  case  of  Fraenkel  a 
gall-stone  was  lodged  in  the  ampulla  of  Vater,  while  in 


156  DISEASE    OF   THE    PANCREAS. 

that  of  Flexner  gall-stones  were  present  in  the  common 
bile  duct  near  its  termination.  In  these  cases  there  can 
be  little  doubt  that  a  gall-stone  compressed  the  pan- 
creatic duct.  Temporary  presence  of  a  large  calculus 
in  the  same  position  would  have  a  similar  effect ;  and 
in  the  following  case  fat  necrosis  was  found  near  the 
pancreas,  though  the  stone  which  had  produced  the 
lesion  had  made  its  way  into  the  intestine  and  was 
lost. 

Case  IV. — Woman,  aged  fifty  years.  Anatomical  Diagnosis. — 
Cholelithiasis,  calculi  in  the  gall-bladder,  cystic,  hepatic,  and 
common  ducts.  Adenocarcinoma  of  the  gall-bladder.  Jaundice. 
Chronic  interstitial  pancreatitis.      Peripancreatic  fat  necrosis. 

The  much-contracted  gall-bladder  and  the  hepatic  and  cystic  ducts 
are  filled  with  facetted  calculi.  The  common  bile  duct  contains  two 
stones,  each  about  one  centimetre  in  diameter,  but  none  are  present 
near  its  termination,  where  the  wall  is  somewhat  thickened  and 
fibrous.  The  pancreas  is  the  seat  of  chronic  interstitial  inflamma- 
tion, and  foci  of  fat  necrosis  occur  in  the  neighborhood  of  the 
gland. 

Both  inflammation  of  the  pancreas  and  necrosis  of  fat 
were  doubtless  due  to  the  passage  of  one  or  more  cal- 
culi through  the  diverticulum  of  Vater,  and  were  the 
result  of  duct-obstruction. 

The  not  infrequent  association  of  fat  necrosis  and 
chronic  interstitial  pancreatitis  admits  a  similar  expla- 
nation. In  two  cases  to  be  cited  in  discussing  chronic 
interstitial  pancreatitis  both  conditions  occur,  but  are 


FAT    NECROSIS.  157 

unaccompanied  by  any  obstruction  of  the  large  ducts. 
The  presence  of  newly-formed  contracting  fibrous 
tissue  affords  abundant  opportunity  for  constriction 
of  the  smaller  ducts.  In  one  of  these  cases  many 
such  ducts  were  on  microscopic  examination  found 
widely  dilated  and  filled  with  stagnant  secretion.  Local 
obstruction  to  the  outflow  of  the  pancreatic  secretion 
doubtless  causes  its  diffusion  into  the  adjacent  fat,  thus 
producing  foci  of  necrosis  ;  but,  as  I  have  mentioned 
before,  induration  of  the  interstitial  tissue  probably 
tends  to  inhibit  dissemination  of  the  lesion. 

In  some  of  the  foregoing  experiments,  as  I  have 
pointed  out,  it  is  probable  that  the  pancreatic  secretion 
passes  directly  from  the  duct  into  the  surrounding 
tissue,  this  being  notably  true  in  the  experiment  in 
which  the  duct-ends  were  transplanted  into  the  subcu- 
taneous fat.  Somewhat  similar  conditions  have  occa- 
sionally been  observed  in  human  cases.  Necrosis  of  the 
pancreatic  tissue  has  in  certain  instances,  as  in  those 
described  by  Chiari,  Fraenkel,  and  Korte,  caused  such 
disintegration  of  the  organ  that  the  ruptured  duct 
communicated  directly  with  the  cavity  of  the  bursa 
omentalis,  in  which  the  pancreas  lay.  Fat  necrosis 
was  present  in  the  wall  of  the  cavity,  and  was 
widely  distributed  in  the  abdominal  fat.  The  remark- 
able case  of  Chiari,  in  which  the  pericardial  and  sub- 
pleural  fat  contained  foci  of  necrosis,  belongs  to  this 
group. 


158  DISEASE    OF   THE    PANCREAS. 

In  the  majority  of  cases  fat  necrosis  is  associated 
with  hemorrhagic  pancreatitis  or  with  its  sequel,  so- 
called  gangrenous  pancreatitis.  Experimental  hemor- 
rhagic inflammation  produced  by  injecting  into  the 
organ  a  variety  of  substances,  of  which  the  common 
characteristic  is  an  ability  to  injure  the  parenchyma  of 
the  gland,  is  accompanied  by  disseminated  fat  necrosis. 
Here  fat  necrosis  is  the  result  of  a  lesion  which  per- 
mits diffusion  of  pancreatic  secretion  from  the  injured 
parenchyma  into  the  surrounding  tissue.  A  similar 
explanation  is  applicable  to  the  human  cases.  Where 
hemorrhagic  pancreatitis  is  caused  by  a  small  calculus 
lodged  in  the  diverticulum  of  Vater,  an  additional 
factor  is  involved.  Since  the  calculus  occludes  the 
duodenal  orifice  of  the  duct,  secretion  from  uninjured 
parts  of  the  gland  is  dammed  back,  and  its  diffusion 
into  the  surrounding  fat  is  facilitated  by  partial  necrosis 
of  the  parenchyma. 

Parapancreatic  Fat  Necrosis. — The  not  infrequent 
occurrence  of  minute  foci  of  fat  necrosis  in  and  upon 
the  pancreas  was  first  noted  by  Balser ;  the  condition, 
which  may  be  designated  parapancreatic  fat  necrosis, 
was  fcmnd  in  five  of  twenty  bodies  which  he  examined. 
On  account  of  their  small  size,  seldom  more  than  a  mil- 
limetre in  diameter,  and  their  limited  distribution,  they 
are  frequently  overlooked,  but  otherwise  agree  in 
character  with  the  lesion  which,  owing  to  its  greater 
extent  and  distribution,  has  been  designated  dissemi- 


FAT   NECROSIS.  I^^ 

nated  fat  necrosis.  Langerhans  found  these  minute 
foci  of  necrosis  in  four  of  twenty-eight  autopsies,  Kasa- 
hara  once  in  eighty-three  cases,  Chiari  twenty-three 
times  in  seventy-five  autopsies,  Williams  eight  times  in 
one  hundred.  The  change  has  been  thought  to  occur 
unassociated  with  lesions  of  the  pancreas.  Langer- 
hans believed  that  it  might  result  from  post-mortem 
action  of  the  pancreatic  juice  ;  and  in  support  of  this 
suggestion  Williams  states  that  the  pancreatic  cells 
near  the  areas  of  fat  necrosis  show  evidence  of  self- 
digestion. 

From  a  study  of  seventy-five  cases,  Chiari  reached 
the  conclusion  that  in  about  one-half  of  all  subjects  the 
pancreas  at  the  time  of  death  has  the  capability  of 
causing  digestion  of  its  own  substance.  This  con- 
dition of  self-digestion  may  be  observed  in  autopsies 
performed  only  a  few  hours  after  death,  and  has  no 
relationship  to  putrefaction,  from  which  it  can  be  readily 
distinguished.  The  conditions  upon  which  it  depends 
are  not  known.  Advanced  self-digestion  affects  the 
entire  substance  of  the  organ,  which  becomes  flaccid  in 
consistence  ;  and  in  sections  prepared  for  microscopic 
examination  nuclei  are  unstained,  so  that  the  tissue  has 
a  homogeneous  appearance.  The  change  affects  the 
interstitial  tissue  as  well  as  the  secreting  parenchyma. 
In  many  cases  self-digestion  is  limited  to  small  areas. 
When  the  organ  undergoes  putrefaction,  nuclear  sub- 
stance,  on  the   contrary,  is    not  dissolved,    but,   being 


l6o  DISEASE    OF   THE    PANCREAS. 

fragmented,  appears  as  fine  particles  scattered  through- 
out the  tissue  ;  bacteria  can  be  readily  found. 

The  frequent  occurrence  of  advanced  self-digestion 
of  the  pancreas,  unaccompanied  by  any  evidence  of  fat 
necrosis,  shows  that  post-mortem  contact  with  the 
pancreatic  ferments  is  insufficient  to  produce  the 
change.  When,  moreover,  fat  removed  from  the  body 
is  exposed  to  the  action  of  pancreatic  tissue,  alterations 
comparable  to  those  associated  with  this  form  of  ne- 
crosis do  not  occur. 

Chiari  believes  that  self-digestion  of  the  pancreas 
so  frequently  observed  at  autopsy  may  set  in  shortly 
before  death,  occurring  as  an  ante-mortem  or  agonal 
change.  Extravasation  of  blood  into  the  partially 
digested  tissue  can  occur,  he  thinks,  only  before  death, 
and  when  present  gives  evidence  that  self-digestion  has 
begun  ante-mortem.  Partial  destruction  of  the  paren- 
chyma would  thus  afford  opportunity  for  diffusion  of 
fat-splitting  ferment  into  the  surrounding  fat.  Under 
such  conditions  it  appears  probable  that  fat  necrosis 
might  occur,  and  in  the  following  instance  the  lesion 
accompanied  self-digestion  associated  with  multiple 
hemorrhages. 

Case  V. — Man,  aged  fifty-three  years.  Anatomical  Diagnosis. — 
Emphysema  of  the  lungs  ;  hypertrophy  of  the  right  side  of  the  heart ; 
chronic  passive  congestion  of  the  viscera  ;  self-digestion  of  the  pan- 
creas, with  multiple  ecchymoses ;   parapancreatic  fat  necrosis. 

The  pancreas  is  very  soft,  and  in  the  interstitial  tissue  are  scat- 


FAT   NECROSIS.  l6l 

tered  ecchymoses.  Upon  the  surface  of  the  organ  occur  very  small, 
opaque,  yellow  foci  of  fat  necrosis.  Microscopic  examination  shows 
the  existence  of  advanced  self-digestion,  with  hemorrhage  here  and 
there  into  the  interstitial  tissue. 


Where  parapancreatic  fat  necrosis  occurs,  micro- 
scopic examination  of  the  pancreas  may  demonstrate 
the  presence  of  a  well-marked  lesion  previously  unob- 
served by  the  naked  eye.  It  has  been  mentioned 
that  foci  of  fat  necrosis  more  or  less  disseminated 
may  accompany  chronic  interstitial  pancreatitis,  and  are 
doubtless  the  result  of  local  duct-obstruction.  Similar 
foci  limited  to  the  pancreas  may  be  so  minute  that 
they  deserve  the  designation  parapancreatic.  Cases 
XI.  and  XIII.,  to  be  described  later,  are  examples  of 
this  condition. 

In  other  instances  it  is  not  improbable  that  minute 
foci  of  necrosis  follow  duct-obstruction,  which  pre- 
sumably has  occurred  only  a  few  hours  before  death. 
In  several  cases  which  I  have  examined  the  pancreatic 
duct  has  been  filled  with  a  very  viscid  secretion  con- 
taining numerous  desquamated  cells.  It  appears  that 
the  pancreatic  secretion  shortly  before  death  has  under- 
gone a  change,  in  consequence  of  which  it  flows  with 
much  difficulty.  Stagnation  and  slight  diffusion  of  the 
products  of  secretion  are  probably  responsible  for  the 
insignificant  fat  necrosis  which  occurs.  The  following 
case  illustrates  this  condition  : 


1 62  DISEASE   OF   THE    PANCREAS. 

Case  VI. — Woman,  aged  fifty  years.  Anatomical  Diagnosis. — 
Chronic  nephritis ;  large  red  kidneys.  Hypertrophy  and  dilatation 
of  the  heart ;  general  anasarca.     Parapancreatic  fat  necrosis. 

The  pancreas  is  firm  and  apparently  normal.  In  the  fat,  upon 
its  surface,  and  in  the  interstitial  tissue  are  small,  conspicuous, 
opaque,  white  areas  of  necrosis.  The  duct  of  Wirsung  is  filled 
with  very  viscid,  pearly-white,  semifluid  material,  which,  examined 
microscopically,  contains  columnar  epithelial  cells  in  great  quantity. 

The  parapancreatic  foci  of  fat  necrosis  so  frequently 
observed  at  autopsy  are  referable  to  a  variety  of 
conditions, — for  example,  to  chronic  inflammation  of 
the  pancreas,  to  partial  duct-occlusion,  and  with  much 
probability  to  other  causes,  among  which  agonal  self- 
digestion  of  the  pancreas  has  a  place.  Neverthe- 
less, in  its  essential  features  the  lesion  resembles 
more  widely  distributed  necrosis,  and  is  doubtless 
produced  by  the  penetration  of  the  fat-splitting  fer- 
ment of  the  pancreatic  juice  into  living  adipose  tissue. 


CHAPTER    VI  I. 

THE    VARIETIES    OF    CHRONIC    INTERSTITIAL    PANCREATITIS. 

The  causes  and  varieties  of  chronic  interstitial  pan- 
creatitis have  been  little  studied,  and  slight  attention  has 
been  given  to  the  classification  of  various  types.  The 
lesion  is  seldom  associated  with  such  definite  symptoms 
that  it  is  recognizable  during  life,  and  even  at  autopsy 
the  condition  is  frequently  overlooked.  Though  chronic 
inflammation  of  the  pancreas  has  not  the  importance  of 
similar  changes  in  the  liver  and  kidneys,  its  relation  to 
diabetes  mellitus  makes  it  worthy  of  detailed  considera- 
tion. Indeed,  study  of  the  lesion  has  contributed  im- 
portant facts  to  the  knowledge  of  this  disease. 

The  etiology  of  interstitial  inflammation  is  often  ob- 
scure. Chronic  pancreatitis  is  not  infrequently  second- 
ary to  changes  in  the  intestine,  the  bile  passages,  and 
the  liver.  As  with  other  glands,  there  is  more  than 
one  path  by  which  inflammatory  irritants  may  reach 
the  organ  :  by  way  of  the  duct,  from  the  blood-vessels, 
and  possibly  from  the  lymphatic  vessels.  Obstruction 
to  the  outflow  of  the  gland  secretion,  here  as  elsewhere, 
is  followed  by  chronic  inflammatory  changes.  The  pan- 
creatic duct  opening  with  the  common  bile  duct  upon 
the  mucous  membrane  of  the  duodenum  is  subject  to 

ascending  infection   both  from  the  intestine  and   from 

163 


1 64  DISEASE    OF   THE   PANCREAS. 

the  biliary  passages  when  inflamed.  Bacteria,  their 
toxic  products,  and  injurious  substances  taken  as  food, 
reaching  the  gland  by  way  of  the  blood,  may  cause 
chronic  inflammation  ;  alcohol,  syphilis,  and  tuberculosis 
are  believed  to  produce  the  lesion.  Alterations  of  the 
vessel  walls,  notably  arterial  sclerosis,  causing  grave 
disturbances  of  nutrition,  are  thought  to  have  the  same 
result. 

Acute,  rapidly  destructive  lesions  of  the  pancreas — for 
example,  hemorrhagic  pancreatitis — affect  the  various 
elements  of  the  gland  almost  simultaneously,  and  dis- 
integration of  greater  or  less  extent  results.  When 
the  organ  is  attacked  by  the  less  active  irritants  which 
produce  chronic  inflammation,  the  different  histological 
constituents  of  the  gland  are  given  greater  opportunity 
to  exhibit  differences  in  their  ability  to  withstand  the 
destructive  process.  The  islands  of  Langerhans  do 
not  always  show  alterations  corresponding  to  those 
which  occur  in  the  tissue  about  them,  often  persisting 
though  the  adjacent  parenchyma  is  destroyed.  More- 
over, while  in  one  variety  of  chronic  inflammation  they 
are  but  little  implicated  in  the  sclerotic  process,  in 
another  they  may  be  markedly  affected.  It  becomes 
of  interest,  therefore,  to  study  the  relation  of  these 
bodies  to  the  various  forms  of  chronic  pancreatitis  that 
are  distinguishable. 

That  form  of  chronic  inflammation  which  occurs 
during  fetal  life,  and  is  associated  with  other  manifes- 


VARIETIES   OF   CHRONIC   PANCREATITIS.         165 

tations  of  congenital  syphilis,  presents  histological  feat- 
ures which  distinguish  it  from  the  chronic  pancreatitis  of 
adult  life.  It  is  a  disease  of  the  developing  organ,  and 
may  appropriately  be  first  considered. 

Congenital  Syphilitic  Pancreatitis. 

Birch-Hirschfeld  first  drew  attention  to  the  frequency 
with  which  the  pancreas  is  affected  by  congenital  syph- 
ilis, and  described  the  lesion  so  accurately  that  nothing 
had  been  added  to  our  knowledge  of  it  until  the 
appearance  of  the  article  of  Schlesinger,  who  made 
a  systematic  study  of  the  condition, 

Birch-Hirschfeld  found  the  pancreas  affected  in 
thirteen  of  twenty-three  cases  of  congenital  lues,  but 
subsequent  observers  have  found  the  lesion  much  less 
frequently,  and,  indeed,  Birch-Hirschfeld,  studying  a 
second  group  of  cases,  found  changes  in  the  organ 
only  twenty-nine  times  in  one  hundred  and  twenty-four 
syphilitic  new-born.  Schlesinger  in  six  instances  found 
the  enlarged  firm  organ  the  seat  of  a  diffuse  interstitial 
pancreatitis  characterized  by  proliferation  of  interlobular 
and  interacinar  tissue  penetrating  at  times  between  the 
cells  of  the  acini.  This  inflammatory  new  growth  is 
followed,  he  thinks,  by  destruction  of  the  parenchy- 
matous elements,  which,  though  they  do  not  exhibit 
appearances  of  degeneration,  atrophy  and  disappear. 
The  growth  of  interstitial  tissue,  he  finds,  has  its  origin 
about  the  blood-vessels,  and  the  arteries  are  the  seat  of 


1 66  DISEASE    OF   THE    PANCREAS. 

a  syphilitic  periarteritis,  the  adventitia  being  infihrated 
with  lymphoid  cells.  As  the  lesion  progresses  the  cap- 
illary net-work  about  the  acini  disappears.  Schlesin- 
ger  has  observed  that  the  islands  of  Langerhans  are 
neither  invaded  by  the  new  growth  of  interstitial  tissue 
nor  implicated  in  the  atrophy  which  affects  the  cells  of 
the  acini. 

Histological  details  observed  in  two  instances  of 
congenital  syphilis  of  the  pancreas  are  here  recorded  ; 
the  relation  of  the  islands  of  Langferhans  to  the  inflam- 
matory  process  is  of  interest. 

Case  VII. — Infant,  lived  three  hours;  length  of  body  forty 
centimetres.  Anatomical  Diagnosis. — Congenital  syphilis;  inter- 
stitial pneumonia  ;  interstitial  pancreatitis :  splenic  tumor ;  chronic 
perisplenitis. 

Microscopic  Examination  of  the  Pancreas. — The  interstitial  tissue  is 
greatly  increased  at  the  expense  of  the  parenchyma,  and  the  lobules, 
composed  of  a  few  acini,  are  irregularly  scattered  in  dense  cellular 
stroma.  The  smallest  ducts,  beset  with  acini  along  their  course, 
terminate  in  a  group  of  acini  which,  though  much  less  numerous 
than  those  ordinarily  forming  a  lobule,  are  of  normal  size,  and  are 
composed  of  cells  showing  no  evidence  of  degeneration.  The  inter- 
stitial tissue  between  groups  of  lobules  is  very  rich  in  cells  of 
lymphoid  and  epithelioid  types.  Particularly  numerous  about  the 
blood-vessels  are  cells  having  the  characteristics  of  the  plasma  cells 
of  Unna.  Cells  with  eosinophilic  granules  are  also  abundant.  A 
conspicuous  feature  of  the  histological  picture  is  the  presence  of  com- 
pact round  masses  of  cells  embedded  in  the  interstitial  tissue.  By 
the  character  of  the  cells  and  by  their  arrangement  in  columns  these 
structures  are  identified  as  islands  of  Langerhans.     Though  they  are 


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Fig.  14. — Congenital  syphilitic  pancreatitis  (Case  VII.).     Showing  a  cell-column  of  an  island 
of  Langerhans  in  continuity  with  a  small  duct. 


VARIETIES    OF    CHRONIC    PANCREATITIS.         167 

embedded  in  the  stroma,  which  separates  widely  the  neighboring- 
acini,  they  are  not  invaded  by  the  inflammatory  change.  At  times 
it  is  demonstrable,  most  conveniently  in  serial  sections,  that  these 
islands  are  in  continuity  with  the  ducts  and  acini  of  the  gland 
(see  Fig.  14).  At  the  periphery  of  the  island  one  of  the  columns 
projects  beyond  the  general  circular  outline  and  is  continuous  with 
epithelial  cells  which,  staining  less  brightly  with  eosin,  are  arranged 
about  a  lumen  and  are  in  turn  continuous  with  adjacent  acini.  In 
many  instances,  however,  an  island  traced  through  a  series  of 
sections  is  found  completely  isolated  in  the  fibrous  tissue. 

Case  VIII. — Infant,  lived  four  hours  ;  length  of  body  fifty  centi- 
metres. Afiatomical  Diagnosis. — Congenital  syphilis;  pemphigus 
neonatorum ;  interstitial  pneumonia ;  interstitial  hepatitis  and  pan- 
creatitis ;  splenic  tumor. 

Microscopic  Examination  of  the  Pancreas. — The  interstitial  tissue 
is  greatly  increased  and  the  parenchyma  is  in  great  part  replaced 
by  it.  The  new  tissue  is  very  cellular,  but  the  cells  are  for  the 
most  part  of  the  epithelioid  type,  and  accumulations  of  round  cells 
are  not  found.  Plasma  cells  and  cells  with  eosinophilic  granu- 
lations are  rarely  seen.  The  acini  form  small  groups  which  may  be 
regarded  as  primary  lobules,  though  the  acini  composing  them  are 
much  less  numerous  than  those  of  a  normal  lobule.  Islands  of 
Langerhans  are  conspicuous  as  compact  round  masses  of  epithelial 
cells  and  are  scattered  abundantly  throughout  the  organ.  The  fibrous 
tissue  is  often  concentrically  arranged  about  these  interacinar  islands, 
and  at  times  they  are  completely  isolated.  Not  infrequently,  however, 
as  in  Case  VII.,  they  are  in  continuity  with  the  neighboring  acinar 
tissue  ;  a  double  row  of  cells  is  found  to  be  continuous  on  the  one 
hand  with  a  cell  column  of  the  island,  on  the  other  with  a  small  duct. 

The  preceding  cases  apparently  represent  different 
stages  of   the   syphilitic    lesion.     In    Case  VII.   prolif- 


1 68  DISEASE    OF   THE   PANCREAS. 

crating  fixed  tissue  cells  are  very  abundant,  while  cells, 
in  part  at  least,  of  vascular  origin — namely,  plasma 
cells  and  eosinophiles — are  numerous,  and  the  condition 
may  be  interpreted  as  the  active  stage  of  a  chronic 
inflammatory  process.  In  Case  VIII.,  though  intersti- 
tial tissue  is  more  abundant  and  the  persistent  paren- 
chymatous elements  are  more  scattered,  cells  of  the 
lymphoid  type  are  few  in  number,  while  plasma  cells 
and  eosinophiles  are  almost  absent.  The  process  here 
is  more  advanced  and  is  no  longer  active. 

A  conspicuous  feature  in  both  cases  is  the  presence 
of  numerous  islands  of  Langerhans  surrounded  by 
newly-formed  stroma,  but  uninvaded  by  it.  In  many 
instances  the  islands  are  found  to  be  in  continuity  with 
the  secreting  structures  of  the  gland  (Fig.  14).  A  cell 
column  of  the  island  is  continuous  with  a  small  duct, 
which  is  in  turn  beset  with  acini ;  the  lumen  of  the 
duct  does  not  penetrate  into  the  island,  but  disappears 
at  the  periphery. 

Birch-Hirschfeld,  finding  the  pancreas  of  the  syphilitic 
fetus  rarely  affected  unless  it  had  survived  the  full 
period  of  uterine  development,  came  to  the  conclusion 
that  the  condition  has  its  onset  during  the  last  months 
of  fetal  life.  Schlesinger,  however,  cites  the  cases  of 
Miiller  and  Mraczek,  in  which,  at  the  fifth  month  of 
development,  advanced  lesion  of  the  organ  occurred, 
and  from  his  own  experience  concludes  that  the  pan- 
creas may  be  affected  as  early  or  as  late  as  other  organs. 


VARIETIES    OF    CHRONIC    PANCREATITIS.         169 

Since  the  pancreas  arises  as  an  outgrowth  from  the 
intestinal  canal,  development  of  its  parenchyma  takes 
place  in  a  mass  of  mesoblastic  stroma  which  is  replaced 
as  the  growth  of  the  gland  proceeds.  At  an  early 
period  of  development — for  example,  during  the  fifth 
month  of  fetal  life — acini  form  small  groups  widely 
separated  by  embryonic  connective  tissue.  In  my  two 
cases  of  syphilitic  pancreatitis  the  parenchyma  presents 
the  appearance  observed  about  the  fifth  month  of  de- 
velopment, save  that  the  islands  of  Langerhans,  which 
are  inconspicuous  in  the  undeveloped  organ,  are 
marked  features  in  the  syphilitic  pancreas.  In  neither 
of  the  syphilitic  cases  was  it  possible  to  observe 
degenerative  changes  in  the  cells.  The  acini  form 
irregular  groups  containing  much  fewer  members  than 
ordinarily  compose  a  fetal  lobule,  or,  as  in  the  de- 
veloping organ,  from  dilatations  upon  the  sides  of 
the  small  ducts. 

It  is  probable,  therefore,  that  the  disease,  like  many 
other  syphilitic  lesions,  is  one  of  the  interstitial  tissue, 
and  changes  in  the  parenchyma  result  not  so  much 
from  destruction  of  the  parenchyma  as  from  interfer- 
ence with  its  growth.  The  similarity  between  the 
syphilitic  and  the  undeveloped  organ  may  be  thus 
explained.  The  development  of  the  individual  cell 
is  not  retarded,  and  islands  of  Langerhans  are  the 
result  of  an  early  cell-differentiation  ;  but  in  many 
instances  islands  remain  in  continuity  with  the  tubular 


170  DISEASE    OF   THE   PANCREAS. 

structures  from  which  they  had  their  origin.  Often, 
however,  the  connecting  strand  of  cells  is  no  longer 
discoverable,  and  the  interacinar  islands  resemble  those 
ordinarily  observed  in  the  organ  at  the  end  of  fetal 
development. 

Chronic  Pancreatitis  of  the  Developed  Organ. 

Several  types  of  chronic  pancreatitis  affecting  the 
fully-developed  organ  have  been  described,  and  with 
the  experimental  demonstration  of  a  relation  between 
the  pancreas  and  carbohydrate  metabolism  numerous 
attempts  have  been  made  to  distinguish  a  variety  of  the 
lesion  constantly  associated  with  diabetes  mellitus.  A 
classification  of  these  various  forms  of  chronic  inflam- 
mation based  upon  etiological  data,  though  desirable, 
would  be,  with  our  present  knowledge,  as  unsatisfac- 
tory as  a  similar  classification  of  the  varieties  of  hepatic 
cirrhosis.  From  an  experimental  study  Carnot  reaches 
the  conclusion  that  pancreatitis  may  result  {a)  from 
mechanical  cause, — for  example,  obstruction  of  the  pan- 
creatic ducts, — from  the  action  [b)  of  toxic  material, 
or  ((t)  of  micro-organisms  carried  to  the  gland  by  the 
blood,  or  by  the  lymph,  or  by  way  of  the  duct.  Such  a 
classification  does  not  aid  in  the  interpretation  of  lesions 
observed  at  autopsy,  the  etiological  factors  concerned 
being  in  many  instances  obscure. 

In  some  examples  of  chronic  pancreatitis  fibrous 
tissue  between  the  lobules  is  increased  ;  in  others  the 


VARIETIES    OF    CHRONIC    PANCREATITIS.         171 

interacinar  tissue  shows  marked  proliferation  ;  occa- 
sionally individual  cells  are  apparently  separated  by 
strands  of  fibrous  tissue.  Corresponding-  types  of  in- 
flammation have  been  described  as  interlobular,  peri- 
acinous,  and  monocellular. 

It  has  been  thought  that  the  increase  of  interstitial 
tissue  may  have  at  times  a  constant  relation  to  the 
blood-vessels  or  to  the  ducts,  being  due,  in  part  at  least, 
to  proliferation  of  the  connective  tissue  about  these 
structures.  Lemoine  and  Lannois  have  described  peri- 
vascular interstitial  pancreatitis.  From  a  study  of  four 
cases  of  chronic  inflammation  associated  with  diabetes 
they  have  thought  that  the  new  growth  of  fibrous  tissue 
has  its  origin  in  the  walls  of  the  blood-vessels.  They 
find  about  the  vessels  masses  of  sclerotic  tissue  send- 
ing processes  between  the  acini  and  even  separating 
the  individual  cells  (sclerose  unicellulaire).  G.  Hoppe- 
Seyler  has  described  chronic  interstitial  changes  which 
he  thinks  are  the  result  of  arterial  sclerosis.  The  paren- 
chyma, he  believes,  undergoes  degeneration  as  a  con- 
sequence of  disturbed  nutrition,  but  no  anatomical  rela- 
tion exists  between  the  vessels  and  the  newly-formed 
tissue.  Chronic  pancreatitis  in  a  case  described  by 
Rosenthal  was  accompanied  by  what  he  regards  as 
alterations  of  the  lymph-vessels  (lymphangitis  prolifer- 
ans),  indicative,  he  thinks,  of  a  probable  syphilitic  origin. 

In  the  instances  of  chronic  inflammation  of  the 
pancreas  which  have  been   available  for  my  study  no 


172  DISEASE    OF   THE    PANCREAS. 

constant  relation  has  been  discoverable  between  the 
newly-formed  tissue  and  the  veins,  arteries,  lymph-ves- 
sels, or  ducts,  and  there  is  no  evidence  that  the  process 
had  its  orig-in  about  these  structures. 

Two  types  of  interstitial  inflammation  are,  however, 
distinguishable.  On  the  one  hand,  though  the  sclerosis 
is  never  accurately  confined  to  one  locality,  it  may  be 
conspicuous  between  the  lobules,  the  intralobular  or 
interacinar  tissue  being  little,  if  at  all,  increased.  On 
the  other  hand,  the  interlobular  tissue  may  be  only 
slightly  altered,  while  fibrous  tissue  which  replaces  the 
parenchyma  separates  individual  acini.  In  the  first  case 
the  lobulation  of  the  gland,  which  is  normally  obscure, 
becomes  more  conspicuous,  and  wide  bands  of  sclerotic 
tissue  separate  groups  of  lobules.  The  lobules  are 
invaded  in  greater  or  less  degree  by  the  newly-formed 
stroma,  and  often  entire  lobules  are  in  process  of  disin- 
tegration and  replacement,  but  the  progress  of  the 
lesion  has  been  apparently  inward  from  the  periphery 
of  the  lobule.  With  the  second  type  of  chronic  inflam- 
mation the  lobulation  of  the  gland  is  not  accentuated  ; 
new  fibrous  tissue,  primarily  within  the  lobule,  has  a 
diffuse  character  and  a  net-work  of  irregular  fibrous 
strands,  which  vary  much  in  thickness,  contains  the 
oflandular  acini  in  its  meshes. 

If  chronic  pancreatitis  is  well  advanced,  the  organ 
may  present  gross  appearances  characteristic  of  one 
or  other  variety  of  interstitial  inflammation.     When  the 


VARIETIES    OF    CHRONIC    PANCREATITIS.         173 

interlobular  tissue  is  the  seat  of  predominant  change, 
the  orland  is  hard  and  dense  and  has  a  nodular  or 
granular  surface.  On  section  the  tissue  has  a  compact, 
homogeneous  appearance,  loose  areolar  tissue  between 
secondary  and  tertiary  lobules  having  been  replaced  by 
scar-like  sclerotic  bands.  When,  on  the  other  hand, 
there  is  a  diffuse  increase  of  the  interacinar  stroma,  the 
organ  tends  to  become  tough  rather  than  hard.  Not 
infrequently,  however,  the  pancreas  affected  with  either 
variety  of  inflammation  may  be  so  little  altered  that  the 
lesion  is  recognized  only  upon  microscopic  examination. 
Abundant  fat  infiltrating  the  newly-formed  tissue  be- 
tween lobules  or  acini  may  obscure  the  gross  character- 
istics of  both  types.  Such  fat  often  contains  small  foci 
of  necrosis. 

The  two  types  of  chronic  interstitial  inflammation — 
(a)  interlobular  and  (d)  interacinar — characterized  by  the 
primary  localization  of  the  lesion  present  other  histo- 
logical peculiarities.  Of  much  interest  is  the  different 
relation  which  they  bear  to  the  islands  of  Langerhans, 
and  it  is  desirable  to  study  separately  the  changes 
affecting  these  bodies  in  the  two  conditions.  The  cases 
which  have  been  studied  exhibit  individual  differences, 
and  in  a  few  instances  the  histological  details  will  be 
briefly  described. 

Ckromc  Interlobular  Pancreatitis. — Sclerosis  of  the 
pancreas,  produced  by  obstruction  of  the  duct,  belongs 
to   the   interlobular  type  of  chronic  inflammation.     Its 


174  DISEASE    OF   THE   PANCREAS. 

definite  causation  as  well  as  certain  histological  features 
serve  to  distinguish  it  from  inflammatory  changes  of 
which  the  etiology  is  more  obscure.  The  pathogenesis 
of  the  lesion  is  not,  however,  clearly  understood. 
Carnot  has  summarized  the  possible  factors  which  have 
a  part  in  its  production.  Retained  secretion,  he  believes, 
has  a  toxic  action  upon  the  parenchymatous  cells. 
Obstruction  to  the  outflow  of  fluid  from  the  ducts  favors 
the  entrance  of  bacteria  from  the  duodenum.  Carnot 
suggests,  moreover,  that  reflex  nervous  stimuli,  which 
normally  reach  the  secreting  cells,  are  no  longer  capable 
of  exciting  normal  functional  activity,  and  deprived  of 
this  influence,  the  cells  atrophy,  as  do  muscle  fibres  after 
section  of  their  motor  nerve. 

Since  the  cells  forming  the  islands  of  Langerhans 
have  no  communication  with  the  ducts  and  take  no 
part  in  producing  the  pancreatic  juice,  the  possible 
factors  mentioned  would,  if  active,  affect  primarily  the 
acini  and  only  secondarily,  if  at  all,  the  interacinar 
islands. 

In  the  cases  which  I  have  studied  varying  degrees  of 
atrophy  and  sclerosis  have  followed  partial  or  complete 
occlusion  of  the  pancreatic  ducts.  The  occurrence  of 
an  active  chronic  inflammatory  process  is  shown  by  the 
presence  of  numerous  lymphoid  cells,  plasma  cells,  and 
eosinophiles  in  the  interstitial  tissue.  The  most  marked 
increase  of  fibrous  tissue  is  between  the  lobules,  but 
acini  with  atrophied  nuclei  and  dilated  lumina  are  not 


VARIETIES   OF    CHRONIC    PANCREATITIS.         175 

infrequently    separated    by    new    tissues.      Islands    of 
Langerhans,  however,  are  completely  unaltered. 

The  following  case  illustrates  an  advanced  stage  of 
interlobular  inflammation,  the  consequence  of  duct- 
obstruction. 

Case  IX. — The  patient,  a  woman,  aged  sixty  years,  began  about  one 
year  before  her  death  to  suffer  with  symptoms  of  obstruction  in  the 
common  bile  duct.  At  operation  performed  by  Dr.  Halsted  ^  a 
carcinoma  of  the  bile  papilla  and  diverticulum  of  Vater  was  found 
and  removed.  The  biliary  and  pancreatic  ducts  were  transplanted 
into  the  duodenum.  Subsequently  an  anastomosis  was  made  between 
the  gall-bladder  and  duodenum. 

Anatomical  Diagnosis. — Recurrent  carcinoma  of  the  duodenum ; 
metastases  in  the  liver ;  occlusion  of  the  pancreatic  duct ;  chronic 
interstitial  pancreatitis  ;  biliary  fistula. 

Pancreas. — On  the  left  lateral  wall  of  the  duodenum  is  a  crater- 
like ulcer  with  raised  edges  abutting  upon  the  head  of  the  pancreas. 
The  pancreatic  duct  is  included  in  the  carcinomatous  tissue  at  the 
base  of  the  ulcer.  The  duct  is  greatly  dilated  and  the  pancreas  is 
small  and  sclerotic. 

Microscopic  Examination. — The  parenchyma  of  the  head  and 
body  has  been  almost  completely  replaced  by  dense  fibrous  tissue 
which  contains  fat  in  considerable  quantity.  Small  isolated  masses 
of  glandular  tissue  still  persist  and  are  subdivided  into  lobules  by 
penetrating  strands  of  fibrous  tissue.  The  stroma  is  in  great  part 
very  dense  and  poor  in  cells.  The  small  ducts  are  dilated.  The 
persistent  glandular  tissue  is  in  part  normal  in  appearance,  but  in 
other  situations  is  undergoing  disintegration,  so  that  the  connective 

^The  history  of  this  case  is  described  by  Dr.  Halsted  in  the 
"Bulletin  of  the  Johns  Hopkins  Hospital,"  1900,  xi.  4. 


176  DISEASE    OF   THE    PANCREAS. 

tissue  not  infrequently  marks  out  areas  which  correspond  apparently 
to  lobules,  but  contain  only  a  few  atrophied  acini  composed  of  flat- 
tened cells  about  a  dilated  lumen.  Here  the  inflammatory  process 
is  active ;  the  connective  tissue  separating  the  atrophic  acini  is  very 
cellular  and  contains  many  lymphoid  cells,  plasma  cells,  and  eosino- 
philes. 

Islands  of  Langerhans,  more  abundant  in  the  tail  and  body  than 
in  the  head,  are  almost  unaltered,  and  are  not  invaded  by  the  newly- 
fomied  fibrous  tissue  which  surrounds  them  and  isolates  the  much 
changed  acini  (see  Fig.  15).  About  an  unaltered  island  may  be 
found  only  a  few  acini  to  indicate  that  it  was  formerly  embedded  in 
the  parenchyma,  while  elsewhere  in  the  dense  fibrous  bands  are  seen 
isolated  structures  of  which  the  cells  do  not  differ  in  character  or 
arrangement  from  those  of  the  interacinar  islets.  Such  islands,  though 
surrounded  by  sclerotic  tissue,  are  not  invaded  by  it,  and  their  cells, 
which  are  normal  in  appearance,  form  columns  separated  by  delicate 
capillary  vessels. 

These  isolated  islands,  however,  finally  undergo  degenerative 
changes.  They  may  be  diminished  in  size  and  distorted.  The 
cells,  particularly  at  the  periphery,  crowded  together,  become  smaller, 
and  their  nuclei,  also  smaller  than  usual,  are  often  irregular  in  shape 
and  stain  deeply.  Further  changes  are  followed  with  difficulty, 
since  the  much  altered  groups  of  cells  are  hardly  recognizable  as 
islands  of  Langerhans.  Small  groups  of  epithelial  cells,  separated 
by  strands  of  connective  tissue,  probably  represent  a  late  stage  of 
atrophy  and  precede  their  final  disappearance  and  replacement  by 
fibrous  tissue. 

When  advanced  chronic  pancreatitis  has  followed 
obstruction  of  the  ducts,  the  organ  is  densely  sclerotic, 
glandular  tissue  having  been  replaced  in  very  large  part 
by  fibrous  stroma.     Small    masses    of  relatively   well- 


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Fig.  15.— Chronic  interstitial  pancreatitis  following  duct-obstruction  (Case  IX. ).  showing  islands 
of  Langerhans  unchanged  though  embedded  in  sclerotic  tissue. 


VARIETIES   OF   CHRONIC   PANCREATITIS.         177 

preserved  parenchyma,  little  if  at  all  invaded,  are  em- 
bedded in  fibrous  tissue  which  contains  almost  no 
epithelial  elements. 

Areas  are  seen  where  disintegrationof  the  glandular 
substance  is  in  active  progress,  and  here  lymphoid 
cells  are  present  in  large  numbers.  A  striking  feature 
of  the  process  is  the  abundance  of  plasma  cells  of 
Unna,  with  which  are  many  cells  containing  eosinophilic 
granulations.  The  scattered  acini  show  the  atrophic 
changes  previously  described.  The  islands  of  Langer^ 
hans  which  occur  in  this  altered  glandular  tissue  are 
unchanged,  and,  even  though  the  neighboring  acini  are 
widely  separated  by  inflammatory  new-growth,  are  unin- 
vaded  (see  Fig.  15).  The  secreting  tissue  about  them 
finally  disappears,  and  they  remain  completely  isolated 
in  the  stroma,  not  infrequently  the  only  vestiges  of 
parenchymatous  tissue  in  wide  sclerotic  bands.  In  a 
section  from  such  an  area  these  isolated  islands  of  Lan- 
gerhans  may  be  very  numerous  ;  and  since  the  sclerotic 
tissue  occupies  less  space  than  the  acini  which  it  has 
replaced,  they  appear  to  be  much  more  abundant  than 
in  the  normal  glandular  parenchyma. 

In  animals,  after  experimental  ligation  of  the  ducts, 
the  islands  of  Langferhans  show  the  same  resistance 
observed  in  human  cases.  Schulze  tied  a  ligature 
tightly  about  the  pancreas  in  guinea-pigs,  and  found  that, 
though  the  secreting  parenchyma  distal  to  the  ligature 
underwent   inflammatory  atrophy,    islands   of   Langer- 


178 


DISEASE    OF   THE    PANCREAS. 


hans  persisted  unaltered  in  the  newly-formed  stroma. 
Ssobolew,  in  a  large  number  of  experiments  performed 
on  rabbits,  dogs,  and  cats,  obtained  similar  results.  In 
the  pancreas  of  a  rabbit  which  lived  four  hundred  days 
after  operation,  fibrous  stroma  about  the  pancreatic 
duct  contained,  he  states,  only  islands  of  Langerhans. 

As  it  is  improbable  that  the  vessels  supplying  the 
islands  with  blood  remain  unchanged  in  the  indurated 
stroma,  it  can  hardly  be  doubted  that  the  nutrition  of 
their  cells  suffers.  The  new  tissue,  growing  older, 
apparently  contracts  and  compresses  them  ;  their  cells 
become  smaller,  the  nuclei  are  small,  irregular,  and 
stain  deeply.  Such  interacinar  islands  finally  disappear, 
being  replaced  by  fibrous  tissue,  which  may  contain  an 
occasional  isolated  group  of  much  atrophied  cells,  or 
may  be  completely  devoid  of  these  structures. 

The  islands  of  Langerhans  resist  the  sclerotic  process 
which  follows  the  damming  back  of  secretion  upon  the 
gland,  and  finally  suffer  only  when  the  acini  are  almost 
entirely  destroyed  and  replaced  by  dense  scar-like 
tissue.  Not  concerned  in  the  production  of  the  pan- 
creatic juice,  they  are  not  exposed  to  its  injurious 
action  when  its  outflow  is  obstructed.  The  changes 
which  completely  isolated  islands  finally  undergo  are,  it 
appears,  due  to  compression  by  the  contracting  scar- 
like tissue  in  which  they  are  embedded  and  to  altera- 
tions of  their  blood-vessels.  Doubtless  the  rich  vascu- 
lar system  of  the  parenchyma  is  in  large  part  obliterated 


VARIETIES    OF    CHRONIC    PANCREATITIS.         179 

when  the  acini  are  replaced  by  interstitial  tissue,  and 
consequently  the  net-work  of  vessels  within  the  island, 
which  freely  anastomose  with  the  adjacent  capillaries, 
is,  as  the  process  advances,  less  freely  supplied  with 
blood. 

Chronic  interlobular  pancreatitis  may  be  the  result 
of  some  condition  other  than  duct-obstruction.  As- 
cending infection  along  the  pancreatic  duct  is  associated 
with  alterations  similar  to  those  just  described,  but  the 
lesion  is  usually  less  severe  ;  and  though  wide  inter- 
lobular bands  separate  relatively  well-preserved  lobules 
and  groups  of  lobules,  the  parenchyma  is  subject  to  less 
wide-spread  destruction.  Nevertheless,  secreting  acini 
in  places  atrophy  and  disappear,  but  the  islands  of 
Langerhans  maintain  to  the  process  the  same  relation 
which  is  observable  when  the  lesion  follows  occlusion 
of  the  duct.  Though  the  neighboring  acini  have  un- 
dergone marked  degenerative  changes,  the  islands  of 
Langerhans  are  unaltered.  Here,  also,  anatomical  pe- 
culiarities serve  to  explain  their  greater  resistance  to 
the  inflammatory  process  :  (i)  Their  vascular  supply  is 
richer  than  that  of  the  adjacent  acini.  (2)  Since  the 
ducts  do  not  penetrate  them,  they  are  less  exposed  to 
the  action  of  irritants  which  reach  the  gland  by  way  of 
the  duct.  (3)  Since  the  islands  of  Langerhans  are 
situated  within  the  lobules  and  frequently  near  their 
centre,  they  are  protected  from  a  lesion  which  pro- 
gresses from  the  periphery  inward. 


l8o  DISEASE   OF   THE   PANCREAS. 

Chronic  Interacinar  Pancreatitis. — The  type  of  pan- 
creatitis which  maybe  conveniently  designated  "inter- 
acinar" is  characterized  by  the  presence  of  newly- 
formed  tissue  within  the  lobules.  The  lesion  is  diffuse 
but  somewhat  irregular  in  distribution  ;  at  one  point 
there  may  be  thickening  of  the  connective-tissue  net- 
work supporting  the  acini,  while  elsewhere  occur  com- 
pact bands  or  small  masses  of  stroma.  Though  the 
interlobular  tissue  is  not  unaffected  by  the  inflam- 
matory change,  its  proliferation  is  not  a  constant 
feature  of  the  histological  picture.  The  lobulation  of 
the  gland  is  not  accentuated,  as  with  the  interlobular 
type,  but,  on  the  contrary,  is  obscured,  since  masses 
and  strands  of  new  tissue  within  the  lobules  make  in- 
conspicuous the  interlobular  boundaries.  This  type  is 
much  less  common  than  the  perilobular  form,  and  has 
occurred  in  only  nine  of  my  thirty  cases.  One  of  these 
was  associated  with  the  condition  of  general  pigmenta- 
tion to  which  von  Recklinghausen  gave  the  name  hsem- 
ochromatosis,  and,  differing  slightly  from  the  other  cases, 
it  will  be  considered  subsequently.  The  following  cases 
exemplify  the  lesion  : 

Case  X. — Clinical  History. — The  patient,  a  man  aged  forty-nine 
years,  gave  no  history  of  alcoholic  excess.  The  present  illness 
began  twenty  months  before  death  with  polyuria.  Much  weight 
had  been  lost.  A  year  and  a  half  before  death  the  spleen  was 
palpable,  and  haematemesis  occurred  at  intervals.  At  this  time 
the  urine  contained  3.5  to  3.8  per  cent,   of  sugar.     The  patient  was 


VARIETIES   OF   CHRONIC    PANCREATITIS. 


I8l 


readmitted  to  the  hospital  four  days  before  his  death  with  ascites 
and  dilated  superficial  abdominal  veins.  The  urine  contained  2.5 
per  cent,  of  sugar. 

Anatomical  Diagnosis. — Chronic  interstitial  pancreatitis;  cirrhosis 
of  the  liver.  Thrombosis  of  the  portal,  splenic,  and  mesenteric 
veins  ;  hemorrhagic  infarction  of  the  intestine.  Acute  serofibrinous 
and  purulent  peritonitis  ;  acute  splenic  tumor. 

Pancreas. — The  organ  is  small  and  firm  in  consistence. 

Microscopic  Examination. — The  interstitial  tissue  is  greatly  in- 
creased and  is  richly  infiltrated  with  fat.  Almost  every  acinus  is  in 
greater  or  less  degree  surrounded  by  fibrous  tissue,  but  the  lobulation 
of  the  parenchyma  is  not  more  distinct  than  usual.  In  many  places 
the  glandular  tissue  of  a  limited  area  is  almost  completely  replaced, 
being  represented  only  by  widely  separated  atrophic  acini.  The  new 
growth  of  tissue,  which  is  often  conspicuous  about  the  ducts  and 
blood-vessels,  bears  no  constant  relation  to  these  structures. 

Islands  of  Langerhans  are  very  abundant,  and  are  sharply  out- 
lined by  fibrous  tissue,  concentrically  arranged,  which  forms  coarse 
capsules,  separating  them  from  adjacent  acini.  There  is,  moreover, 
proliferation  of  the  connective  tissue  within  them ;  along  the  capil- 
laries irregularly  spindle-shaped  nuclei  are  more  numerous  than 
usual,  and  there  is  an  increased  amount  of  fibrillated  material.  The 
cells  of  the  islands  are  often  very  small,  and  their  nuclei,  diminished 
in  size,  stain  deeply ;  they  are  closely  packed  together  to  form  wide, 
irregular  columns.  Not  infrequently  the  interacinar  fibrous  tissue  is 
much  more  abundant  in  the  immediate  neighborhood  of  the  islands 
than  elsewhere,  and  here  forms  a  close  net-work  of  coarse  strands 
with  small  meshes  containing  atrophied  acini. 

Case  XI. — Clinical  History. — The  patient,  a  man,  aged  forty- 
seven  years,  has  used  alcohol  in  excess.  His  health  has  been  good 
until  six  months  before  death.  For  three  months  symptoms  of  dia- 
betes mellitus  have  been  present.     The  body  weight  has  been  fairly 


1 82  DISEASE    OF   THE   PANCREAS. 

well  retained.  The  patient  was  in  the  hospital  five  days  preceding 
his  death,  during  which  time  the  urine  contained  from  0.6  to  2.5  per 
cent,  of  sugar ;  acetone  was  present.  He  was  dull,  drowsy,  and  at 
times  delirious. 

Anatomical  Diagnosis. — Chronic  interstitial  pancreatitis  ;  cirrhosis 
of  the  liver ;  chronic  passive  congestion  of  the  spleen  ;  ascites.  Para- 
pancreatic  fat  necrosis.     Arterial  sclerosis  ;  gangrene  of  the  leg. 

Pancreas. — The  organ,  weighing  one  hundred  and  eight  grammes, 
is  firm,  particularly  at  its  splenic  end.  Here  lobulation  is  obscured 
and  the  texture  of  the  glandular  tissue  is  compact.  In  the  fat 
within  and  about  the  organ  are  small,  opaque,  yellowish-white  areas. 

Microscopic  Examination. — Throughout  the  organ  there  is  an 
abundant  diffuse  new  growth  of  interstitial  tissue  between  the  indi- 
vidual acini.  The  new  tissue  is  poor  in  cells,  and  consists  in  great 
part  of  white  fibres  loosely  packed  together.  In  the  meshes  of  the 
irregular  net-work  which  it  forms  lie  acini,  or  small  groups  of  acini, 
which  are  often  atrophic  in  appearance.  Acini  of  large  size,  con- 
taining many  centro-acinar  cells,  are  seen. 

Islands  of  Langerhans  are  abundant  in  the  tail,  and  are  of  large 
size.  They  are  frequently  surrounded  by  a  thick  capsule  of  fibrous 
tissue,  and  are  invaded  by  the  new  tissue,  which  often  forms  coarse 
ingrowths  along  their  capillaries  (see  Fig.  16).  Though  all  the 
islands  are  surrounded  by  dense  sclerotic  tissue,  some  are  only  slightly 
invaded.  Where  marked  thickening  occurs  about  their  capillary 
vessels,  the  epithelial  cells  are  diminished  in  size  and  are  closely 
packed  together ;  the  nuclei  are  small  and  stain  deeply. 

While  with  the  interlobular  type  of  chronic  interstitial 
inflammation  the  islands  of  Langerhans  are  unaffected 
by  the  sclerosis  and  show  changes  only  when  the  lesion 
has  reached  a  very  advanced  stage,  in  the  cases  just 
recorded  a  new  growth  of  tissue  within  the  lobules  and 


^I=e  V 


•^   -••^~  Z')'  •  '^*j5  -'-7  * 


Fig.  i6. — Chronic  interstitial  pancreatitis  of  interacinar  type  (Case  XI.),  showing  the  invasion 
of  an  island  of  Langerhans  by  the  inflammatory  process. 


VARIETIES    OF   CHRONIC    PANCREATITIS.         183 

between  the  acini  invades  the  interacinar  islands.  The 
latter  are  almost  constantly  surrounded  by  fibrous 
tissue,  which  forms,  as  it  were,  a  capsule  separating 
them  from  adjacent  acini,  which  are  themselves  abnor- 
mally separated  from  one  another.  About  the  capilla- 
ries of  the  island  there  is  a  proliferation  of  interstitial 
tissue  forming  coarse  strands  between  the  columns  of 
cells. 

With  chronic  pancreatitis  of  the  interlobular  type 
proliferation  of  interstitial  tissue  occasionally  occurs  be- 
tween the  acini,  but  is  usually  confined  to  the  periphery 
of  the  lobule.  The  islands  of  Langerhans,  situated  in 
the  midst  of  the  secreting  tissue,  often  near  the  centre 
of  more  or  less  clearly  defined  lobules,  are  surrounded 
by  the  least  changed  acini.  With  the  interacinar  type 
of  sclerosis  the  condition  is  different ;  In  the  immediate 
neighborhood  of  the  island  may  be  found  the  greatest 
proliferation  of  stroma,  and  the  acini,  separated  from  It 
and  from  one  another  by  coarse  strands  of  white  fibrous 
tissue,  are  then  more  atrophic  than  those  at  a  greater 
distance.  When  the  inflammatory  process  affects  pri- 
marily the  periphery  of  the  lobule  and  progresses 
towards  the  centre,  the  islands  are  affected  only  when 
the  lesion  is  very  advanced ;  but  when  the  change 
occurs  difliisely  within  the  lobule,  all  parts  are  equally 
affected,  and  the  Islands  suffer  in  common  with  the  acini. 
Indeed,  it  often  appears  that  the  favorite  seat  of  the 
lesion  is  the  Immediate  neighborhood  of  these  bodies. 


CHAPTER   VIII. 

THE    ETIOLOGY    OF    CHRONIC    INTERSTITIAL     PANCREATITIS. 

Elsewhere  I  have  classified  cases  of  chronic  intersti- 
tial pancreatitis  studied  in  the  pathological  laboratory 
of  the  Johns  Hopkins  Hospital.^  Clinical  records  were 
obtainable,  and  in  every  instance  material  was  pre- 
served for  microscopic  examination.  Of  thirty  cases, 
including  one  not  previously  considered,  seventeen 
occurred  in  males  and  thirteen  in  females.  The  age 
of  the  affected  individuals  was  as  follows : 


lo  to  20  years 
20  to  30  years 
30  to  40  years 
40  to  50  years 
50  to  60  years 
60  to  70  years 
70  to  80  years 


1  case. 

2  cases. 

2  cases. 
9  cases. 

II  cases. 

3  cases. 
2  cases. 


Twenty  cases,  more  than  two-thirds  the  total  number, 
occurred  between  the  ages  of  forty  and  sixty  years. 


^"The  Causes  and  Varieties  of  Chronic  Interstitial  Inflamma- 
tion," American  Journal  of  the  Medical  Sciences,  June,  1902, 
Twenty-nine  cases  of  chronic  pancreatitis  are  described ;  an  addi- 
tional case  has  been  added  to  the  series.  In  the  present  chapter 
occur  numerous  quotations  from  this  article. 


"JSA. 


ETIOLOGY   OF    CHRONIC   PANCREATITIS.         185 

Obstruction  of  the  Pancreatic  Ducts. — In  ten  cases 
chronic  interlobular  pancreatitis  was  the  result  of  duct- 
obstruction.  Ligation  of  the  duct  in  animals  is  fol- 
lowed  by  chronic  inflammation  ;  in  human  cases  partial 
or  complete  occlusion  may  be  caused  by  pancreatic  cal- 
culi within  the  duct  of  Wirsung,  by  biliary  calculi  within 
the  adjacent  terminal  part  of  the  common  bile  duct,  or 
by  new  growths,  usually  carcinomata,  compressing  or 
invading  the  gland.  The  irritant  action  of  retained 
secretion,  and  in  many  cases,  at  least,  associated  infec- 
tion of  the  obstructed  duct,  are  doubtless  concerned  in 
producing  the  resultant  sclerosis,  but  in  individual  cases 
the  relative  importance  of  these  two  factors  is  difficult 
to  determine. 

In  human  cases  conditions  which  produce  obstruction 
of  the  pancreatic  duct  are  usually  such  as  favor  infec- 
tion. The  pancreas,  it  has  been  shown,  is  provided 
with  two  ducts  which,  in  nine  of  ten  instances,  anas- 
tomose within  the  gland.  The  duct  of  Santorini  is 
occasionally  of  large  size,  in  about  one  of  ten  cases 
even  larger  than  the  duct  of  Wirsung,  and  its  duodenal 
orifice  is  freely  patent.  In  most  subjects,  however,  the 
duct  of  Santorini  is  in  part  rudimentary,  and  its  orifice  is 
too  minute  to  act  as  an  outlet  for  the  entire  pancreatic 
secretion  should  the  duct  of  Wirsung  be  occluded. 

Pancreatic  Calculi. — The  two  cases  to  follow  are 
described  in  order  to  illustrate  the  extreme  degree  of 
sclerosis    which    may    follow    the    presence    of    calculi 


1 86  DISEASE    OF   THE   PANCREAS. 

within  the  pancreatic  ducts.  The  lesion  derives  its  im- 
portance, in  part,  from  the  fact  that  diabetes  meUitus 
occasionally  accompanies  chronic  inflammatory  changes 
due  to  the  presence  of  calculi.  This  relationship  will 
be  discussed  subsequently. 

Case  XII. — Sujnmary  of  Clinical  History. — W.  H.,  male,  aged 
forty-three  years,  had  used  beer  in  large  quantity.  Ten  months 
before  his  death  he  had  had  an  attack  of  jaundice.  Diagnosis  :  Pul- 
monary tuberculosis.     No  symptoms  of  diabetes  were  noted. 

Anatomical  Diagnosis. — Chronic  pulmonary  tuberculosis  \  tuber- 
culous pleurisy.  Cirrhosis  of  the  liver  with  fatty  degeneration. 
Splenic  tumor.  Pancreatic  calculi ;  interstitial  pancreatitis ;  peri- 
pancreatic  fat  necrosis. 

Pancreas. — The  duct  of  Wirsung  and  its  branches  are  much 
distended  by  numerous  calculi.  The  gland-tissue  has  in  large  part 
disappeared,  and  is  replaced  by  interstitial  tissue  containing  abundant 
fat,  in  which  are  opaque,  white  areas  of  necrosis.  The  concretions 
give  the  reactions  of  calcium  carbonate. 

Microscopic  Examination. — The  parenchyma  has  been  in  very 
great  part  replaced  by  dense  fibrous  tissue,  in  which  are  scattered 
foci  of  round  cells.  In  the  head  of  the  organ  are  small  areas  of 
glandular  tissue,  subdivided  by  interlobular  fibrous  strands.  Occa- 
sionally gland  lobules  are  found  in  process  of  disintegration,  atro- 
phied acini  with  dilated  lumina  being  separated  by  newly-formed 
interstitial  tissue.  Numerous  islands  of  Langerhans,  most  abundant 
in  a  section  from  the  splenic  end  of  the  organ,  are  surrounded  and 
isolated  by  newly-formed  stroma,  and  though  the  tissue  about  is 
densely  fibrous,  one  sees  within  the  islands  delicate  capillaries,  often 
distended  with  red  blood-corpuscles.  Occasionally  an  island  has 
the  appearance  of  being  compressed  and  distorted. 


ETIOLOGY    OF    CHRONIC    PANCREATITIS.         187 

Case  XIII. — Summary  of  Clinical  History. — The  patient,  male, 
aged  fifty  years,  gives  a  history  of  alcoholic  excess.  His  illness  began 
five  months  before  its  fatal  termination  with  symptoms  of  pulmonary 
tuberculosis  which  gradually  increased  in  severity.  On  admission  to 
the  hospital,  two  months  after  the  onset  of  his  illness,  the  urine 
contained  5.2  per  cent,  of  sugar.  When  given  a  diet  very  poor  in 
carbohydrates  (v.  Noorden's  standard  diabetic  diet),  sugar  dis- 
appeared from  the  urine,  and  reappeared  only  when  carbohydrates 
were  added, — ninety  grammes  of  white  bread  to  the  daily  diet. 

Anatomical  Diagnosis. —Yzxvzx^dXxc  calculi;  chronic  interstitial 
pancreatitis ;  parapancreatic  fat  necrosis.  Chronic  pulmonary  tuber- 
culosis.    Chronic  diffuse  nephritis  ;  large  white  kidneys. 

Pancreas. — The  organ  is  much  diminished  in  size  and  is  tough  and 
fibrous.  Atrophy  is  so  marked  that  the  body  is  merely  a  narrow 
isthmus  connecting  the  head  and  tail.  The  duct,  slightly  enlarged, 
contains  a  number  of  gritty,  yellow  calculi,  the  largest  being  the  size 
of  a  split  pea.  On  section  the  tissue  has  a  grayish-yellow  color, 
and  small  masses  of  parenchyma  project  between  thick  bands  of  con- 
nective tissue.      Minute  opaque  points  suggest  fat  necroses. 

Microscopic  Examination. — Sclerosis  is  far  advanced  and  is  most 
marked  in  the  tail  of  the  organ,  where  glandular  acini  are  almost 
entirely  absent.  The  glandular  tissue  which  still  persists  occurs  as 
small,  compact  masses  embedded  in  dense  stroma.  At  the  periphery 
of  this  relatively  normal  parenchyma  are  found  lobules  or  parts  of 
lobules  in  process  of  disintegration  and  replacement  by  the  inter- 
stitial tissue.  Completely  isolated  in  the  dense  stroma  of  the  body 
and  tail  are  numerous  masses  of  polygonal  cells  occupying  conspicuous, 
sharply  outlined,  round  or  oval  spaces  in  the  sclerotic  tissue.  These 
islands  of  Langerhans  are  so  thickly  scattered  that  in  places  ten  or 
twelve  may  be  seen  in  the  field  of  the  low  power.  In  the  surround- 
ing tissue  lymphoid  and  plasma  cells  are  numerous,  and  it  may  be 
assumed  the  inflammatory  process  is  still  active. 


1 88  DISEASE    OF    THE    PANCREAS. 

Such  persistent  islands  may  be  finally  implicated  in  the  general 
sclerosis.  An  increase  of  fibrous  tissue  occurs  along  their  capillaries, 
which  become  coarse  strands  subdividing  the  body  into  small  masses 
of  atrophied  cells.  One  finds  elsewhere  broad  bands  of  dense 
fibrous  tissue  containing  no  epithelial  elements  or  only  an  occa- 
sional compressed  group  of  cells  similar  to  those  which  form  the 
islands. 

Biliary  Calculi. — Riedel  has  directed  attention  to  the 
fact  that  induration  of  the  head  of  the  pancreas,  at  times 
observed  during  operations  undertaken  for  the  removal 
of  gall-stones,  may  readily  be  mistaken  for  malignant 
growth.  Carcinoma  of  the  pancreas  was  suspected  in 
three  of  one  hundred  and  twenty-two  such  operations, 
but  the  subsequent  history  of  his  patients  disproved 
this  supposition,  and  chronic  pancreatitis  was  found  in 
one  patient  who  died.  Mayo  Robson  has  described  two 
similar  cases,  in  one  of  which  chronic  inflammation  was 
demonstrated  at  autopsy,  while  in  the  second  malignant 
growth  was  excluded  by  recovery  of  the  patient. 

The  followinof  case  illustrates  the  relation  of  chronic 
interlobular  pancreatitis  to  cholelithiasis  and  demon- 
strates a  mechanism  by  which  the  change  is  pro- 
duced. 

Case  XIV. — The  patient,  a  man,  aged  sixty-three  years,  after  re- 
peated attacks  of  jaundice  underwent  operation,  but  on  account  of 
dense  adhesions  it  was  not  possible  to  explore  the  bile  passages.  Symp- 
toms of  cirrhosis  subsequently  developed,  and  the  abdomen  was  tapped 
several  times.  The  urine  did  not  contain  sugar.  The  patient  had 
used  alcohol  in  excess. 


ETIOLOGY   OF   CHRONIC    PANCREATITIS.         189 

Anatomical  Diagnosis. — Cholelithiasis;  contraction  of  the  gall- 
bladder ;  calculus  in  the  common  bile  duct ;  dilatation  of  bile  ducts  ; 
cirrhosis  of  the  liver  ;  chronic  interlobular  pancreatitis  ;  serofibrinous 
peritonitis  ;  chronic  nephritis  ;  arterial  sclerosis. 

Near  the  termination  of  the  common  bile  duct,  but  just  above  its 
junction  with  the  duct  of  Wirsung,  is  a  large,  oval  gall-stone,  firmly 
wedged  into  the  common  duct  in  such  a  position  as  to  compress 
the  terminal  part  of  the  pancreatic  duct,  which,  as  it  enters  the 
diverticulum    of  Vater,    passes   immediately   below   the    stone   (see 


Fig.  17. — Biliary  calculus  (actual  size)  which,  in  Case  XIV.,  completely  filled 
the  diverticulum  of  Vater  and  occluded  the  duct  of  Wirsung;  chronic  interstitial 
pancreatitis  resulted.  Compare  with  the  much  smaller  calculus  which  in  Case  I. 
(see  Fig.  12)  caused  acute  hemorrhagic  pancreatitis. 


Fig.  17).  The  pancreas  is  firm  in  consistence  and  compact  in 
texture.  The  papilla  of  the  duct  of  Santorini  is  not  demonstrably 
patent. 

A  small  calculus,  as  I  have  shown  in  a  previous 
chapter,  may  lodge  at  the  orifice  of  the  diverticulum  of 
Vater,  and,  occluding  it,  may  convert  the  comm^on  bile 
duct  and  the  duct  of  Wirsung  into  a  continuous  channel, 
thus  causing  the  penetration  of  bile  into  the  pancreas 
and  consequent  hemorrhagic  pancreatitis.  A  larger 
calculus  present  in  the  diverticulum  of  Vater  or  in  the 
common  bile  duct,  slightly  above  its  junction  with  the 
pancreatic  duct,  may  temporarily  or  permanently  com- 
press   the    latter   and   produce    chronic   inflammatory 


IQO 


DISEASE    OF   THE   PANCREAS. 


changes  resembling  those  which  follow  ligation  of  the 
duct  in  animals. 

Doubtless  bacterial  infection  often  plays  a  part  in  the 
production  of  the  lesion,  and  in  two  additional  cases  of 
chronic  interlobular  pancreatitis  the  bile  passages  con- 
taining gall-stones  were  the  seat  of  acute  suppurative 
inflammation  ;  opportunity  was  thus  afforded  for  as- 
cending infection  of  the  duct  of  Wirsung.  In  neither 
case  was  a  calculus  found  compressing  the  pancreatic 
duct,  but  at  some  previous  time  during  the  expulsion 
of  a  stone  into  the  intestine  partial  occlusion  may  have 
occurred.  Since,  however,  the  pancreatic  ducts  were 
the  seat  of  acute  inflammatory  changes  it  is  not  im- 
probable that  chronic  inflammation  may  have  been  the 
result  of  infection  originating  in  the  acutely  inflamed 
bile  passages. 

Malignant  Growth. — In  five  of  my  cases  chronic  in- 
terstitial pancreatitis  was  caused  by  a  malignant  growth 
compressing  or  invading  the  organ.  In  the  following 
case,  which  may  serve  as  an  illustration  of  this  condi- 
tion, a  primary  carcinoma  of  the  pancreas  arising  in 
the  head  of  the  gland  compressed  the  duct  of  Wirsung 
and  produced  chronic  interstitial  inflammation  accom- 
panied by  the  formation  of  cysts. 

Case  XV. — The  patient,  female,  aged  forty-one  years,  became  jaun- 
diced nine  months  before  her  death.  A  tumor  mass  was  palpable  in 
the  umbilical  region.     Autopsy  was  performed  by  Dr.  Flexner. 

Anatomical  Diagnosis. — Adenocarcinoma  of  the  pancreas,   com- 


ETIOLOGY    OF    CHRONIC    PANCREATITIS. 


191 


pressing  the  bile  and  pancreatic  ducts ;  jaundice  ;  chronic  interlobular 
pancreatitis ;  retention  cysts  of  the  pancreas  \  metastatic  carcinoma 
of  the  retroperitoneal  lymph  glands. 

The  tumor,  which  arises  from  the  pancreas,  consists  of  two  masses, 
between  which  the  remains  of  the  head  and  part  of  the  body  lie 
compressed.  A  fibrous  capsule  separates  the  tumor  from  the  glandular 
parenchyma.  Numerous  cysts  about  the  size  of  a  walnut  occupy  the 
body  and  tail,  and  are  present  but  less  numerous  in  the  duodenal  end. 
A  probe  can  be  passed  along  the  compressed  duct. 

In  a  second  case,  previously  described  (Case  IX.), 
advanced  chronic  interstitial  inflammation  followed  the 
development  of  a  carcinoma  of  the  bile  papilla  and 
diverticulum  of  Vater.  Marked  dilatation  of  the  pan- 
creatic duct  gave  evidence  of  its  partial  obstruction. 
Infection  from  the  ulcerated  surface  upon  which  the 
duct  opened  was  with  great  probability  an  important 
factor  in  producing  the  advanced  chronic  interstitial 
inflammation  which  resulted. 

In  three  cases  chronic  inflammatory  changes  were 
associated  with  the  invasion  of  the  gland  by  a  carcino- 
matous new  growth  of  the  stomach.  When  the  head 
of  the  gland  is  invaded  there  is  a  diffuse  interstitial 
change,  but  where,  as  in  two  cases,  the  body  is  invaded 
while  the  head  is  not  in  contact  with  the  tumor, 
inflammatory  alterations  occur  only  in  that  part  of  the 
gland  distal  to  the  point  at  which  the  duct  is  compressed. 
The  carcinomatous  tissue,  moreover,  acts  as  a  local 
inflammatory  irritant  and  in  its  immediate  neighborhood 


192  DISEASE    OF   THE    PANCREAS. 

there  is  proliferation  of  the  stroma  replacing  the 
parenchymatous  elements. 

Ascending  Infection  from  the  Duode^ium  ;  Association 
of  Chronic  Interlobular  Pancreatitis  and  Persistent 
Vomiting. — Under  normal  conditions  the  pancreas,  like 
other  glands  of  the  gastro-intestinal  tract,  is  protected 
against  the  entrance  of  micro-organisms.  The  valve- 
like folds  within  the  diverticulum  of  Vater  prevent  the 
regurgitation  of  material  from  the  duodenum  into  the 
duct,  and  if  after  death  fluid  is  forced  under  considerable 
pressure  into  the  duodenum,  tied  above  and  below  the 
gland,  none  enters  the  duct.  The  flow  of  secretion, 
washing  away  foreign  material,  doubtless  has  a  part  in 
the  protection  of  the  gland. 

Korte  has  produced  chronic  inflammation  of  the  pan- 
creas by  injecting  bacillus  coli  into  the  pancreatic  duct, 
and  has  obtained  a  similar  result  by  injecting  faecal 
materiab  By  an  ingenious  method  Carnot  produced 
conditions  by  which  an  ascending  infection  from  the 
duodenum  results.  A  thread,  inserted  into  the  pan- 
creatic duct,  and  through  its  orifice  into  the  duodenum, 
was  left  fixed  in  this  position.  Advanced  sclerosis  of 
the  gland  resulted,  and  the  walls  of  the  ducts  were 
thickened  and  infiltrated  with  leucocytes,  while  the  in- 
terstitial tissue  of  the  gland  was  much  increased.  In 
another  experiment  Carnot  produced  suppurative  in- 
flammation by  injecting  colon  bacilli  into  the  pancreatic 
duct. 


ETIOLOGY   OF    CHRONIC    PANCREATITIS.         193 

In  four  of  the  thirty  cases  which  I  have  observed, 
advanced  chronic  interstitial  inflammation  has  been 
found  in  individuals  who  during  Hfe  have  suffered  with 
persistent  vomidng.  Since  this  disease  of  the  pancreas 
is  notably  one  of  advanced  life,  twenty-five  of  thirty 
cases  occurring  after  the  age  of  forty  years,  two  such 
cases  in  young  women  suggest  the  presence  of  some 
unusual  etiological  factor.  In  a  third  case  chronic 
pancreatitis  followed  persistent  vomiting  in  a  man 
forty-nine  years  of  age,  who  though  once  addicted 
to  alcohol,  had  for  ten  years  led  a  temperate  life ; 
chronic  gastritis  was  found  at  autopsy.  In  the  fourth 
case  vomiting  accompanied  carcinomatous  constriction 
of  the  terminal  part  of  the  duodenum.  In  all  of 
these  cases  the  clinical  history  affords  evidence  of 
continued  gastric  or  gastro-intestinal  disease, — namely, 
epigastric  pain,  nausea,  and  vomiting.  Since  the  asso- 
ciated conditions  appear  to  favor  infection  of  the  duct, 
the  cases  have  been  described  under  the  present 
heading. 

Case  XVI. — The  patient,  a  deaf  mute,  female,  aged  thirty-one 
years,  entered  the  service  of  Dr.  Osier  complaining  of  "heart- 
burn" and  dyspepsia.  She  states  that  at  the  age  of  twenty-four 
years  she  had  "inflammation  of  the  stomach"  and  was  sick  for 
eight  weeks.  She  has  since  suffered  with  dyspepsia.  She  has  had 
one  living  child  and  three  miscarriages,  and  is  at  present  pregnant. 
Four  days  before  her  admission  she  began  to  vomit ;  the  vomiting 
has  persistently  continued  and  has  recurred  irrespective  of  the  taking 
of   food.     Physical  examination  disclosed    nothing  of   importance. 

13 


194 


DISEASE    OF   THE   PANCREAS. 


After  her  admission  vomiting  was  almost  continuous,  but  examina- 
tion of  the  vomitus  gave  no  noteworthy  information.  In  the  after- 
noon of  the  following  day,  the  patient  becoming  much  weaker  and 
semi-unconscious,  vomiting  ceased.  Owing  to  the  severity  of  the 
symptoms  an  exploratory  laparotomy  was  performed.  The  condition 
after  operation  was  improved  and  there  was  no  return  of  vomiting 
until  twelve  days  later,  when  it  recurred  with  its  previous  persistence. 

The  patient  was  transferred  to  the  obstetrical  ward,  and  it  was  de- 
cided to  empty  the  uterus ;  an  ovum,  two  and  a  half  months  old, 
was  removed.  The  patient  died  on  the  twenty-second  day  after  her 
admission.      Sugar  was  not  found  in  the  urine. 

Anatomical  Diagnosis. — Endometritis  of  the  puerperal  uterus. 
Anomalous  artery,  a  branch  of  the  aorta  penetrating  the  substance 
of  the  right  lung  ;  rupture,  with  formation  of  cavity  containing  blood- 
clots.      Chronic  interlobular  pancreatitis. 

The  condition  of  the  uterus  and  of  the  right  lung  will  not  be 
described.  The  stomach  is  normal,  save  for  the  presence  of  a  few 
submucous  ecchymoses ;  the  duodenum  is  normal  in  appearance. 
The  pancreas  is  almost  board-like  in  consistence,  and  on  microscopic 
examination  the  interlobular  tissue  is  found  to  be  dense  and  fibrous, 
containing  many  spindle-shaped,  lymphoid,  eosinophile,  and  plasma 
cells.  Entire  lobules  are  at  times  partially  destroyed,  a  few  scattered 
acini  remaining  in  the  proliferated  stroma,  but  in  general  the  sharply 
defined  lobules  are  not  invaded  by  the  process. 

Case  XVII. — H.  B.,  female,  aged  twenty-eight  years,  was  ad- 
mitted to  the  service  of  Dr.  Kelly  complaining  of  bleeding  from  the 
vagina.  Her  present  illness  began  ten  months  before  her  admission 
with  sudden  profuse  hemorrhage  from  the  vagina.  An  operation, 
the  nature  of  which  she  did  not  know,  was  performed  five  months 
later,  and  was  followed  by  much  nausea  and  vomiting.  Previous  to 
her  admission  she  had  been  much  nauseated,  and  states  that  even  a 
small  quantity  of  water  might  cause  her  to  vomit,  so  that,   though 


ETIOLOGY    OF    CHRONIC   PANCREATITIS. 


195 


often  hungry,  she  was  afraid  to  eat.  She  has  had  colicky  pains  in 
the  epigastrium.  Vaginal  examination  demonstrated  the  presence  of 
an  inoperable  fungating  carcinoma  of  the  cervix.  The  urine  con- 
tained no  sugar. 

Anatomical  Diagnosis. — Carcinoma  of  the  uterus,  with  metastases 
in  the  broad  ligaments,  pelvic  and  lumbar  lymphatic  glands,  liver, 
and  rectum  ;  double  pyelonephrosis.  Chronic  interlobular  pancrea- 
titis. 

The  pancreas  is  firm  in  consistence  and  on  section  very  compact 
in  texture.  There  are  no  noteworthy  changes  in  the  stomach,  intes- 
tine, or  bile  passages.  Microscopic  examination  of  the  pancreas 
shows  an  abundant  proliferation  of  the  interlobular  tissue,  which  is 
dense  and  fibrous,  but  often  contains  lymphoid  and  plasma  cells  in 
considerable  number. 

Case  XVIII. — The  patient,  male,  aged  forty-nine  years,  was  ad- 
mitted to  the  service  of  Dr.  Osier  complaining  of  rheumatism, 
cough,  shortness  of  breath,  and  indigestion.  He  formerly  used 
alcohol  in  excess,  but  for  the  last  ten  years  had  only  taken  an  occa- 
sional drink.  For  a  year  he  had  had  attacks  of  vomiting  without 
any  apparent  cause  and  with  no  relation  to  the  taking  of  food, 
occurring  sometimes  in  the  morning  before  breakfast.  He  describes 
the  vomitus  as  consisting  in  great  part  of  phlegm.  On  admission 
the  patient  was  a  well-nourished  man  slightly  cyanosed.  The  heart 
was  hypertrophied,  and  a  systolic  murmur  was  present  at  the  apex. 
He  died  on  the  fourth  day  after  admission.  The  urine  contained 
no  sugar. 

Anatomical  Diagfiosis. — Chronic  endocarditis  of  the  mitral  valve  ; 
dilatation  and  hypertrophy  of  the  heart ;  cardiac  thrombi ;  chronic 
passive  congestion  of  the  viscera ;  infarcts  of  the  lungs ;  acute  and 
chronic  gastritis  ;  ulceration  of  the  ileum  and  colon  ;  chronic  inter- 
lobular pancreatitis  with  lipomatosis. 

The  mucosa  of  the  stomach,  covered  by  a  thick  layer  of  tenacious 


196  DISEASE    OF   THE    PANCREAS. 

mucus,  has  a  puffy  appearance  and  is  red  in  color,  studded  with 
small  submucous  ecchymoses.  The  pancreas  weighs  one  hundred  and 
fifty-two  grammes.  The  glandular  tissue  is  in  great  part  replaced 
by  fat.  Microscopic  examination  shows  that  groups  of  lobules  are 
widely  separated  by  adipose  tissue,  while  within  these  groups  indi- 
vidual lobules  are  separated  by  thickened  strands  of  dense  stroma 
containing  many  lymphoid  cells ;  in  places  are  seen  lobules  under- 
going disintegration. 

The  cases  just  described  illustrate  the  occurrence  of 
chronic  interlobular  pancreatitis  in  individuals  who 
during  life  have  suffered  with  persistent  vomiting. 
They  indicate  the .  existence  of  some  relationship  be- 
tween gastro-intestinal  disturbance  and  chronic  lesion 
of  the  pancreas.  It  is  improbable  that  persistent 
vomiting  was  caused  by  pancreatic  disease,  since  in 
many  cases  the  latter  has  existed  unaccompanied  by 
this  symptom.  Persistent  vomiting,  even  though  de- 
pendent upon  disturbances  of  the  reflex  nervous  mech- 
anism, or  upon  the  evacuation  of  toxic  products  into 
the  stomach,  is  indicative  of  some  profound  change  in 
the  organ,  and  has  probably  been  associated  with  con- 
ditions favoring  ascending  infection  of  the  pancreatic 
duct.  The  mechanical  effect  of  vomiting  upon  the 
ducts  and  their  contents  is  difficult  to  determine. 

The  type  of  the  accompanying  pancreatic  lesion 
favors  the  probability  of  infection  by  way  of  the  duct, 
for  here  pancreatitis  is  typically  interlobular  and  resem- 
bles that  observed   in  those  cases   where    infection  of 


ETIOLOGY    OF    CHRONIC    PANCREATITIS.         197 

the  pancreas  has  followed  lesions  of  the  gall-ducts 
with  or  without  duct-obstruction.  This  explanation  is 
further  confirmed  by  the  following  case,  in  which  per- 
sistent vomiting  was  the  result  of  partial  occlusion  of 
the  terminal  part  of  the  duodenum. 

Case  XIX. — Mrs.  F.  G.,  aged  fifty-one  years,  entered  the  service 
of  Dr.  Osier  seven  weeks  before  her  death,  complaining  of  nausea, 
vomiting,  and  loss  of  weight.  Her  uterus  had  been  removed  seven 
years  before  by  Dr.  Kelly  for  carcinoma  of  the  cervix ;  she  had 
since  enjoyed  good  health.  Two  months  before  re-entering  the 
hospital  she  was  attacked  with  very  severe  vomiting,  occurring  often 
five  or  six  times  a  day  and  unaccompanied  by  nausea,  but  preceded 
by  slight  pains  in  the  chest.  Food  caused  no  pain.  While  in  the 
hospital  there  were  frequently  repeated  attacks  of  vomiting,  usually 
at  intervals  of  from  twelve  to  eighteen  hours,  the  vomitus  consist- 
ing of  greenish-yellow  fluid  varying  in  amount  from  a  few  cubic 
centimetres  to  a  litre ;  it  contained  no  blood.  No  sugar  was  found 
in  the  urine. 

Anatomical  Diagnosis. — Recurrent  adenocarcinoma  of  the  retro- 
peritoneal lymphatic  glands  and  of  the  peritoneum  ;  indurated  car- 
cinomatous tissue  constricting  the  duodenum  and  left  ureter  ;  multiple 
abscesses  of  kidney  ;  cystitis  ;  broncho-pneumonia  ;  fatty  degeneration 
of  the  liver ;  fibrous  myocarditis. 

In  front  of  the  sacrum,  near  the  promontory,  are  a  few  enlarged, 
firm,  lymphatic  glands,  which  on  microscopic  examination  are  found 
to  contain  adenocarcinoma.  Indurated  tissue  formed  by  carcino- 
matous cells  embedded  in  dense  stroma  is  found  on  either  side  of 
the  aorta,  at  the  base  of  the  mesentery  where  the  jejunum  emerges, 
and  upon  the  neighboring  peritoneal  surface.  Similar  sclerotic  tissue 
invading  the  wall  of  the  duodenum  at  its  termination  has  contracted 


198 


DISEASE    OF   THE    PANCREAS. 


the  lumen  to  a  diameter  of  twelve  millimetres.  The  constricted 
area  is  not  more  than  one  centimetre  in  length,  and  above  and  below 
the  intestinal  wall  is  soft.  The  pancreas  is  very  firm,  and  upon  the 
surface  individual  lobules  are  sharply  defined.  The  ducts  are  not 
dilated.  Microscopic  examination  shows  an  interlobular  inflam- 
mation of  moderate  intensity,  the  lobulation  being  accentuated  by 
thickened  fibrous  bands  containing  lymphoid,  plasma,  and  eosino- 
phile  cells  in  fair  abundance. 

Alterations  of  the  Blood-  Vessels. — In  the  cases  already- 
considered  chronic  pancreatitis  has  been  secondary  to 
alterations   occurring  in  the  ducts  ;    in   another  group 
of  cases  the   ducts   are   unchanged  and  the  lesion   is 
referable   to   the  blood-vessels   or  to  toxic    substances 
brought  to  the  gland  by  the  blood.      In  the  pancreas, 
as  in  other  organs,  general  arterial  sclerosis  has  been 
thought  to  be  the  cause  of  fibroid  induration,  and  G. 
Hoppe-Seyler   and    Fleiner    have    described    cases    of 
chronic  interstitial  pancreatitis,    attributed  by  them  to 
obliterating     endarteritis.       Both    writers     think    that 
changes  in  the  vessels    are   followed   by  nutritive  dis- 
turbances which  cause  degeneration  of  the  parenchyma 
and  its  replacement  by  fibrous  tissue.     The  condition, 
Fleiner  sugrfirests,  is  analoofous  to  the  contracted  kid- 
ney  which  is  at  times  associated  with  general  arterial 
sclerosis  and  to  changes  in  the  liver,  heart,  and  brain 
following    arterial  disease.     In  three  cases  of  arterial 
sclerosis    Kasahara  found   a  moderate  increase  of  the 
interstitial  tissue  of  the  pancreas,  but  in  other  cases  of 


ETIOLOGY   OF    CHRONIC    PANCREATITIS.         199 

the  same  disease  found  nothing  more  than  thickening 
of  the  blood-vessels. 

In  only  four  cases  of  the  present  series  is  arterial 
sclerosis  sufficiently  marked  to  receive  mention  in  the 
anatomical  diagnosis  made  at  autopsy.  In  the  following 
case  of  diabetes  advanced  arterial  sclerosis  is  accompa- 
nied by  chronic  interacinar  pancreatitis.  Here  both 
gangrene  of  the  foot  and  pancreatic  lesion  are  refer- 
able, in  part  at  least,  to  arterial  sclerosis. 

Case  XX. — The  patient,  a  woman,  aged  sixty-three  years,  entered 
the  Johns  Hopkins  Hospital  suffering  with  gangrene  of  the  right 
foot,  which  had  begun  five  weeks  before.  Sugar  was  discovered  in 
the  urine.  Death  occurred  with  coma  twelve  days  after  admission. 
The  urine,  of  which  the  specific  gravity  was  1024  to  1027,  contained 
sugar,  the  largest  amount  found  being  2.2  per  cent.  ;  preceding  death 
acetone  was  abundant. 

Anatomical  Diagnosis. — General  arterial  sclerosis;  calcification  of 
the  coronary  arteries  and  of  the  right  posterior  tibial  and  dorsalis 
pedis  arteries.  Gangrene  of  the  right  foot.  Chronic  interacinar 
pancreatitis. 

The  pancreas,  weighing  eighty- two  grammes,  is  firm  in  consistence 
and  is  surrounded  and  infiltrated  by  abundant  fat.  The  splenic 
artery  in  contact  with  the  gland  is  tortuous  and  partially  calcified. 
Microscopic  examination  shows  the  presence  of  a  diffuse  increase  of 
the  interacinar  stroma,  more  marked  in  the  tail  than  elsewhere. 
The  newly-formed  tissue  is  poor  in  cells.  The  islands  of  Langerhans 
are  often  surrounded  by  thickened,  capsule-like  strands  of  fibrous 
tissue,  and  similar  proliferation  of  connective  tissue  has  occurred 
along  the  course  of  their  capillary  vessels.  Small  arteries  throughout 
the  parenchyma  not  infrequently  show  obliterating  endarteritis  and 
hyaline  changes  in  the  middle  coat. 


200  DISEASE    OF    THE    PANCREAS. 

Doubtless  arterial  sclerosis  has  a  part  in  the  pro- 
duction of  chronic  pancreatitis,  and  in  the  preceding  case 
it  is  one  of  the  etiological  factors  concerned.  Never- 
theless, the  proportion  of  cases  in  which  arterial  sclerosis 
has  been  present,  five  of  thirty  cases,  cannot  be  regarded 
as  significant  when  one  considers  that  chronic  pan- 
creatitis, with  few  exceptions,  occurs  after  the  age  of 
forty  years.  Advanced  arterial  sclerosis,  moreover,  may 
be  unaccompanied  by  pancreatitis,  and  in  two  cases  not 
included  in  the  present  series  the  arteries  of  the  pancreas 
were  greatly  thickened,  while  only  in  their  immediate 
neighborhood  was  there  proliferation  of  the  interstitial 
tissue. 

A  second  alteration  of  the  blood-vessels  assigned  as 
a  cause  of  chronic  pancreatitis  is  chronic  passive  con- 
gestion. Friedreich  states  that  pancreatitis  is  not  in- 
frequently the  result  of  long-continued  venous  gorging, 
occurring  in  chronic  diseases  of  the  heart,  lungs,  and 
liver.  The  changes,  he  says,  are  usually  slight  and  do 
not  cause  destruction  of  the  glandular  elements,  but 
between  the  acini  are  formed  small  tracts  of  thickened 
connective  tissue,  giving  the  gland  an  increased  tough- 
ness. Small  interstitial  hemorrhages  occur  and  are 
changed  later  into  collections  of  rust-colored  pigment. 

In  the  following  case  the  pancreas  was  the  seat  of  an 
extreme  grade  of  chronic  passive  congestion,  following 
complete  occlusion  of  the  portal  vein  by  a  primary 
carcinoma  of  the  liver. 


ETIOLOGY   OF   CHRONIC    PANCREATITIS.         20 1 

Case  XXI. — Anatomical  Diagnosis. — Primary  carcinoma  of  the 
liver  invading  and  occluding  the  portal  vein;  chronic  passive  con- 
gestion of  the  spleen,  pancreas,  stomach,  and  intestines ;  ascites. 
Chronic  interstitial  pancreatitis  with  pigmentation. 

The  pancreas  is  compressed  by  the  distended  splenic  vein,  and  is 
firm  and  compact  in  texture  and  of  a  uniform  dull  brownish-red 
color.  The  veins  are  widely  dilated,  and  are  occasionally  plugged 
by  carcinomatous  tissue.  There  is  a  slight  increase  of  the  inter- 
lobular tissue,  and  among  the  acini  occur  irregular  patches  of  inter- 
stitial tissue,  poor  in  cells.  Small  hemorrhages  have  in  places 
occurred  into  the  interlobular  tissue,  and  both  here  and  within  the 
secreting  cells  is  found  brown  pigment  which  contains  iron. 

In  the  preceding  case  the  pancreas  is  the  seat  of  a 
sHght  generahzed  increase  of  the  interstitial  tissue  be- 
tween the  acini  as  well  as  between  the  lobules,  but  it 
serves  to  illustrate  how  small  is  the  influence  of  extreme 
chronic  passive  congestion  in  causing  proliferation  of 
the  pancreatic  connective  tissue.  In  two  additional 
cases  of  the  present  series  chronic  passive  congestion 
dependent  upon  a  valvular  lesion  of  the  heart  accom- 
panied chronic  inflammation  of  the  pancreas.  One  of 
these  cases,  Case  XVIII. ,  in  which  gastro-intestinal 
inflammation  coexisted,  has  already  been  described. 
In  the  second  case,  not  cited  in  detail,  inflammatory 
change  cannot  be  attributed  to  chronic  congestion,  since 
at  least  one  other  possible  factor  existed, — namely, 
chronic  lead  poisoning. 

The  frequency  of  chronic  congestion  of  the  abdominal 
viscera,  and  the  relative  infrequency  of  chronic    inter- 


202  DISEASE    OF   THE   PANCREAS. 

stitial  inflammation  of  the  pancreas,  is  evidence  that  the 
former  condition  is  not  commonly  a  cause  of  the  latter. 
Chronic  passive  congestion  may  doubtless  produce 
slight  proliferation  of  the  interstitial  tissue,  but  is  an 
unimportant  factor  in  the  production  of  chronic  pan- 
creatitis. 

In  many  of  the  remaining  cases  belonging  to  the 
present  series  of  thirty  it  is  probable  that  the  lesion, 
like  corresponding  changes  in  the  liver  and  kidney, 
namely,  cirrhosis  of  the  liver  and  chronic  interstitial 
nephritis,  is  caused  by  the  action  of  toxic  substances 
present  in  the  blood.  Various  conditions  presumably 
capable  of  producing  such  substances  have  been  as- 
signed as  the  cause  of  chronic  pancreatitis ;  those 
notably  worthy  of  consideration  are  tuberculosis,  syphi- 
lis, and  alcohol,  named  in  the  probable  order  of  their 
increasing  importance. 

Tuberculosis. — Carnot  has  recently  directed  attention 
to  the  occurrence  of  chronic  pancreatitis  accompanying 
tuberculosis.  The  specific  lesion  of  tuberculosis  is,  he 
thinks,  relatively  uncommon  in  the  gland,  and  in  only  one 
case  has  he  observed  acute  miliary  tuberculosis.  Diffuse 
chronic  interstitial  inflammation  of  the  pancreas  asso- 
ciated with  tuberculous  lesions  of  other  organs  is,  he 
states,  much  more  common,  and  a  number  of  the  older 
writers,  Ancelet,  Vulpian,  Arnozan,  and  Morache,  have 
cited  such  cases.  Carnot  examined  the  pancreas  in 
patients    dying    with    tuberculosis,    and    while   in    the 


ETIOLOGY   OF    CHRONIC    PANCREATITIS.         203 

majority  no  lesion  was  demonstrable,  in  seven  cases  he 
found  a  variable,  usually  moderate  grade  of  chronic 
inflammation  causing,  in  most  cases,  an  increase  of  the 
connective  tissue  normally  present  about  the  vessels 
and  ducts  and  between  the  lobules. 

Carnot  was  able  to  produce  chronic  inflammatory 
changes  in  the  pancreas  of  dogs,  somewhat  varied  in 
extent  and  character,  by  injecting  suspensions  of  the 
bacillus  tuberculosis  into  the  duct  or  into  the  paren- 
chyma of  the  organ,  but  it  was  necessary  to  inject  a 
very  great  quantity  of  the  culture.  A  caseous  abscess 
resulted  in  one  case,  but  in  the  other  experiments  the 
lesion  presented  none  of  the  specific  characters  of  tuber- 
culosis, and  tubercle  bacilli  were  not  demonstrable  in 
the  tissues.  In  a  single  case  localized  sclerosis  was 
produced  by  injecting  into  the  parenchyma  tuberculin 
extracted  from  the  bodies  of  the  dead  bacilli. 

In  the  two  cases  included  in  the  present  series 
chronic  interstitial  pancreatitis  was  found  at  the  autopsy 
upon  individuals  dead  with  advanced  tuberculous 
lesions.  In  one  of  these  cases  miliary  tubercles  were 
found  in  the  pancreas,  but  in  the  second  none  were  found 
in  the  sections  examined.  In  three  additional  autopsies 
performed  in  the  pathological  laboratory  of  the  Johns 
Hopkins  Hospital  tuberculous  lesions  were  present  in 
the  pancreas,  but  there  was  no  generalized  proliferation 
of  the  interstitial  tissue.  The  two  cases  of  chronic 
inflammation    mentioned    give    some    support    to    the 


204  DISEASE    OF    THE    PANCREAS. 

conclusion  of  Carnot  that  in  a  few  instances  generalized 
tuberculosis  is  accompanied  by  chronic  pancreatitis,  but 
they  afford  no  explanation  of  its  occurrence.  The 
condition  may  be  dependent  upon  proximity  to  a  tuber- 
culous lesion,  as  in  one  of  Carnot's  cases,  where  only 
the  splenic  extremity  of  the  gland  in  contact  with  a 
tuberculous  kidney  was  affected,  and  a  similar  explana- 
tion may  be  applicable  to  the  cases  of  Arnozan,  in  which 
chronic  pancreatitis  accompanied  tuberculous  peri- 
tonitis. 

Since  tuberculosis  is,  as  is  well  known,  a  frequent 
complication  of  diabetes,  its  relationship  to  alterations 
of  the  pancreas  are  of  much  interest.  In  the  cases  just 
cited  diabetes  did  not  occur  and  the  lesion  of  moderate 
severity  is  interlobular,  a  type  of  inflammation  accom- 
panied by  diabetes  only  when  very  far  advanced.  There 
is,  it  appears,  no  reason  to  suppose  that  diabetes  may 
be  caused  by  pancreatitis  resulting  from  tuberculosis. 

Syphilis. — The  autopsy  records  of  the  pathological 
laboratory  of  the  Johns  Hopkins  Hospital  furnish  no 
instance  in  which  chronic  pancreatitis  has  been  asso- 
ciated with  visceral  syphilis  ;  and  though  the  literature 
demonstrates  that  the  two  conditions  occur  in  conjunc- 
tion, acquired  syphilis  is  certainly  not  the  most  common 
cause  of  the  lesion,  as  Hansemann,  Kasahara,  and 
other  writers  beheve.  In  only  one  of  the  present  series 
of  cases  was  a  history  of  syphilis  obtained  ;  and  in  this 
case  chronic  pancreatitis  with  formation  of  cysts  was 


ETIOLOGY   OF    CHRONIC    PANCREATITIS. 


205 


caused  by  primary  carcinoma  of  the  pancreas  compress- 
inor  the  duct. 

In  a  case  described  by  Drozda  the  pancreas  was 
represented  by  a  mass  of  indurated  tissue,  in  which 
glandular  structures  were  recognizable  only  in  the  head, 
while  here  and  there  occurred  caseous  Qrummata  em- 
bedded  in  the  fibrous  stroma.  The  liver  was  the  seat 
of  syphilitic  cirrhosis  and  the  stomach  contained  an 
indurated  scar.  In  a  case  of  visceral  syphilis -described 
by  Chvostek  the  tail  of  the  pancreas  was  penetrated 
by  several  sclerotic  bands  of  tissue,  giving  it  a  lobed 
appearance. 

In  these  cases  the  alterations  are  analogous  to  syph- 
ilitic lesions  of  the  liver  and  are  characterized  by  the 
occurrence  of  gummata  or  irregular  scar-like  bands  of 
tissue  penetrating  the  parenchyma  ;  they  differ  from  the 
more  common  lesion,  in  which  there  is  a  diffusely  dis- 
tributed increase  of  the  interlobular  or  interacinar  tissue. 
To  the  latter  type  belongs  apparently  the  case  of  Dieck- 
hoff,  in  which,  though  there  was  a  history  of  syphilis, 
coexisting  carcinoma  of  the  stomach  was  a  possible 
etiological  factor.  In  two  cases  of  chronic  interstitial 
pancreatitis  associated  with  diabetes  Hansemann  ob- 
tained evidence  of  syphilis.  Kasahara  examined  the 
pancreas  in  six  cases  of  acquired  syphilis,  and  in  two 
found  a  moderate  increase  of  the  interstitial  tissue,  in 
two  merely  thickening  of  the  blood-vessels,  and  in  two 
no  alterations. 


2o6  DISEASE    OF   THE    PANCREAS. 

Syphilis  is  no  doubt  a  cause  of  chronic  inflammation 
of  the  gland,  and  the  cases  of  Droza  and  Chvostek  in- 
dicate the  existence  of  a  syphilitic  pancreatitis  charac- 
terized by  the  occurrence  of  scar-like  bands  of  tissue 
which  may  contain  gummata.  The  etiological  relation- 
ship of  syphilis  to  a  diffusely  distributed  interacinar  or 
interlobular  inflammation  is  doubtful. 

Alcohol. — The  common  cause  of  cirrhosis  of  the  liver 
is  excessive  use  of  alcoholic  drinks.  Cirrhosis  is  rela- 
tively infrequent  when  compared  with  the  prevalence 
of  alcoholic  indulgence  ;  but  here,  as  with  many  diseases, 
other  conditions  are  necessary  in  order  that  the  lesion 
may  result.  Alcoholic  excess  is  likewise  regarded  as 
a  frequent  cause  of  chronic  interstitial  pancreatitis,  and 
in  many  instances  a  history  of  alcoholic  indulgence 
can  be  obtained.  Friedreich  found  at  autopsy  upon  a 
drunkard  chronic  pancreatitis,  cirrhosis  of  the  liver,  and 
granular  kidneys.  Chvostek,  Dieckhoff,  and  Oser  have 
described  cases  in  which  cirrhosis  of  the  liver  and 
chronic  pancreatitis  were  associated  in  alcoholics.  In 
eight  of  the  present  thirty  cases  a  history  of  alcoholic 
excess  was  obtained,  but  in  three  of  these  cases  (Cases 
XII.,  XIII.,  XIV.)  chronic  inflammation  of  the  organ  had 
followed  obstruction  of  its  duct  by  biliary  or  pancreatic 
calculi,  and  was  indirectly,  if  at  all,  referable  to  the  use 
of  alcohol. 

In  the  following  case  chronic  interlobular  pancrea- 
titis unaccompanied  by  cirrhosis  of  the  liver  was  found 


ETIOLOGY    OF   CHRONIC   PANCREATITIS.         207 

at   autopsy  in    an    individual  dying  with  delirium    tre- 
mens. 

Case  XXII. — J.  M.,  male,  aged  fifty-three  years,  was  admitted  to 
the  service  of  Dr.  Osier  -with  delirium.  His  Avife,  from  whom  a 
satisfactory  history  was  not  obtained,  stated  that  he  had  been  drink- 
ing very  heavily  for  a  month,  and  on  the  morning  before  his  admis- 
sion became  delirious  and  feverish.  The  patient  was  completely 
unconscious,  the  temperature  rose  to  105.4°  F.,  and  he  died  on  the 
second  day  after  admission. 

Anatomical  Diagnosis. — Bronchitis  and  beginning  aspiration 
pneumonia  ;  acute  diphtheritic  and  hemorrhagic  colitis  ;  fatty  degen- 
eration of  the  liver ;  chronic  interlobular  pancreatitis  ;  fat  necrosis. 

The  pancreas,  of  normal  size,  is  very  firm  in  consistence,  and  the 
interstitial  tissue  appears  to  be  indurated.  The  ducts  are  normal. 
Numerous  small  foci  of  fat  necrosis  occur  about  the  pancreas  and  in 
the  transverse  mesocolon.  Microscopic  examination  shows  a  typical 
chronic  interlobular  pancreatitis,  and  the  interstitial  tissue  contains 
numerous  lymphoid  cells. 

Few  reported  cases  of  chronic  inflammation  of  the 
pancreas  not  dependent  upon  lesions  of  the  duct  are 
described  with  sufficient  detail  to  determine  the  pres- 
ence or  absence  of  an  alcoholic  history,  and  a  review 
of  them  would  afford  statistics  of  little  value.  Alcohol 
beingr  the  common  cause  of  cirrhosis  of  the  liver,  the 
association  of  chronic  pancreatitis  with  this  lesion  is 
significant. 

Association  of  Chronic  Pancreatitis  with  Cirrhosis  of 
the  Liver. — In  the  present  thirty  cases  of  chronic  pan- 
creatitis   cirrhosis    of    the   liver    occurs    in    eight.       In 


2o8  DISEASE   OF   THE    PANCREAS. 

three  of  these  cases  pancreatitis  is  indirectly,  if  at 
all,  related  to  the  lesion  of  the  liver  and  has  followed 
readily  demonstrable  changes  in  the  duct  of  Wirsung. 
The  relationship  of  the  blood-supply  of  the  liver  to  that 
of  the  pancreas  suggests  the  possibility  that  venous  ob- 
struction may  play  a  part  in  the  production  of  pan- 
creatic sclerosis,  but  the  small  influence  which  it  exerts 
has  already  been  pointed  out. 

Chronic  inflammation  of  the  liver  and  pancreas  have 
been  found  associated  by  Friedreich,  Chvostek,  Hanse- 
mann,  Dieckhoff,  Kasahara,  Oser,  and  Lefas.  In  six 
cases  of  chronic  interstitial  hepatitis  Kasahara  found  a 
marked  increase  of  connective  tissue  in  the  pancreas, 
in  two  a  slight  increase,  and  in  two  none  at  all. 

Of  considerable  interest  are  the  observations  of 
Lefas,  who  studied  alterations  of  the  pancreas  accom- 
panying different  varieties  of  hepatic  cirrhosis.  With 
the  so-called  atrophic  or  Laennec's  cirrhosis  he  finds 
that  the  weight  of  the  pancreas  is  often  increased  to 
one  hundred  and  twenty  or  one  hundred  and  thirty 
grammes,  and  the  newly-formed  tissue,  which  is  poor 
in  cells,  is  uniformly  intralobular,  penetrating  the  paren- 
chyma and  isolating  groups  of  acini.  The  point  of 
origin,  he  says,  seems  to  be  the  capillaries,  but  at  an 
advanced  stage  there  is  a  moderate  grade  of  prolif- 
eration about  the  small  veins  and  arteries.  With 
the  so-called  hypertrophic  biliary  cirrhosis  of  Hanot 
the  pancreas  is  not  enlarged,  but  the  interlobular  tissue 


ETIOLOGY   OF    CHRONIC    PANCREATITIS.         209 

is  increased  in  amount  and  in  density,  and  containing 
numerous  cells,  appears  most  altered  about  the  ducts. 
The  cases  of  interstitial  pancreatitis  which  I  have  ob- 
served in  part  confirm  the  observations  of  Lefas,  though 
a  relationship  of  the  newly-formed  tissue  to  the  blood- 
vessels and  ducts  is  not  evident. 

In  two  cases  previously  described  (Cases  X.  and  XI.) 
chronic  interacinar  pancreatitis  accompanied  by  diabetes 
was  associated  with  cirrhosis  of  the  liver  of  the  so- 
called  atrophic  type  of  Laennec.  In  only  one  was  there 
a  history  of  excessive  alcoholic  indulgence. 

An  excellent  illustration  of  the  dependence  of  chronic 
lesions  of  the  liver  and  of  the  pancreas  upon  the  same 
etiological  factor  is  furnished  by  the  disease  of  pig- 
ment metabolism,  first  described  by  von  Recklinghausen, 
haemochromatosis.  In  this  condition,  to  be  described 
subsequently,  an  iron-containing  pigment  is  deposited 
in  the  cells  of  the  liver,  pancreas,  and  various  other 
organs,  and  its  presence  is  associated  with  death  of 
parenchymatous  cells  and  consequent  proliferation  of 
the  stroma.  In  a  case  of  haemochromatosis  (see  Case 
XXXII.)  included  in  the  present  series  cirrhosis  of  the 
liver  is  accompanied  by  chronic  interacinar  pancreatitis, 
resembling,  though  less  advanced,  that  observed  in  the 
two  cases  just  mentioned  (Cases  X.  and  XL). 

In  the  following  case  hypertrophic  cirrhosis  of  the 
type  of  Hanot  was  accompanied  by  interlobular  pan- 
creatitis, as  in  the  cases  described  by  Lefas. 

14 


2IO  DISEASE   OF    THE    PANCREAS. 

Case  XXIII. — The  patient,  male,  aged  fifty -six  years,  admitted 
to  the  service  of  Dr.  Osier,  gives  a  history  of  having  used  whiskey 
in  excess,  usually  taking  from  fifteen  to  twenty-five  drinks  a  day. 
He  denies  having  had  syphilis.  For  the  last  year,  until  a  short  time 
ago,  he  has  had  attacks  of  vomiting,  and  during  the  last  six  months 
has  become  weak  and  short  of  breath.  The  liver  is  enlarged,  and 
there  are  ascites  and  other  evidences  of  portal  congestion.  Sugar 
was  not  found  in  the  urine. 

Anatomical  Diagnosis. — Hypertrophic  cirrhosis  (of  Hanot)  ; 
ascites ;  chronic  passive  congestion  of  spleen ;  chronic  interlobular 
pancreatitis ;   cholelithiasis. 

The  liver,  weighing  two  thousand  eight  hundred  and  eighty 
grammes,  exhibits  the  gross  and  microscopic  appearance  of  hyper- 
trophic cirrhosis  of  Hanot.  The  gall-bladder  contains  many  small 
facetted  calculi.  The  pancreas,  weighing  sixty  grammes,  is  very 
firm  in  consistence  and  evidently  sclerotic.  The  duct  of  Wirsung 
in  the  body  and  tail  of  the  gland  is  dilated,  and  contains  solid  wax- 
like material.  Microscopic  examination  shows  that  the  lobules,  par- 
ticularly in  the  body  and  tail,  are  separated  by  dense  sclerotic  tissue 
showing  little  tendency  to  penetrate  between  the  acini. 

In  the  case  just  described  the  so-called  hypertrophic 
cirrhosis  of  Hanot  was  accompanied  by  interlobular 
pancreatitis  ;  the  condition;  however,  was  complicated  by 
the  presence  of  gall-stones.  In  an  additional  case  in- 
cluded in  my  series  interlobular  pancreatitis  of  moderate 
grade  accompanied  beginning  cirrhosis  in  a  woman 
twenty-two  years  of  age,  and  though  the  hepatic  lesion 
corresponded  to  the  so-called  atrophic  or  Laennec's 
cirrhosis,  the  alteration  of  the  pancreas  differed  from 
that  observed  by  Lefas  and  found  in  Cases  X.  and  XI. 


ETIOLOGY    OF   CHRONIC    PANCREATITIS.         21 1 

It  is  noteworthy,  however,  that  the  lesion  was  asso- 
ciated with  tuberculous  peritonitis,  while  a  variety  of 
chronic  lesions  coexisted  in  other  oro^ans. 

o 

Interacinar  Pancreatitis  of  Obscure  Etiology. — Of  the 
present  series  of  thirty  cases  there  are  five  instances  of 
interacinar  pancreatitis  of  which  the  etiology  is  wholly 
obscure  ;  in  all  of  them  the  lesion  is  of  very  slight  in- 
tensity. In  four  cases  the  islands  of  Langerhans  were 
the  seat  of  a  remarkable  hyaline  change,  and  diabetes 
mellitus  had  resulted.  I  have  described  elsewhere  one 
of  these  cases  in  which,  though  the  islands  of  Langer- 
hans were  almost  uniformly  affected  by  the  degenera- 
tive change,  increase  of  the  interacinar  stroma  was  very 
inconspicuous.  Hyaline  degeneration  of  the  islands 
of  Langerhans  in  association  with  diabetes  has  since 
proved  to  be  of  much  more  frequent  occurrence  than 
was  at  first  suspected,  and  in  addition  to  the  subsequent 
examples  which  have  come  to  my  notice  cases  have 
been  recently  observed  by  Wright  and  Joslin  and  by 
Hertzog,  In  one  of  two  cases  of  Wright  and  Joslin 
and  in  both  cases  of  Hertzog  hyahne  degeneration  of 
the  islands  of  Langerhans  was  associated  with  prolifera- 
tion of  the  interstitial  tissue  of  the  gland. 

In  the  following  case  of  chronic  interacinar  pan- 
creatitis the  islands  of  Langerhans  were  almost  wholly 
unchanged,  but  the  pancreas  was  the  seat  of  a  slight 
interacinar  pancreatitis.  The  case  is  of  interest  be- 
cause diabetes  was  absent.  The  clinical  and  anatomical 
diagnoses  in  this  case  were  as  follows  : 


212  DISEASE    OF   THE    PANCREAS. 

Case  XXIV. — Male,  aged  fifty-eight  years.  Diagnosis. — Inoper- 
able carcinoma  of  rectum  ;  cesophageal  diverticulum.  Inguinal  colos- 
tomy was  performed,  and  later  the  oesophageal  diverticulum,  which 
compressed  the  trachea,  was  removed.  Death  followed  the  latter 
operation. 

Anatouiical  Diagnosis. — Carcinoma  of  rectum  ;  metastases  in  the 
retroperitoneal  lymphatic  glands,  liver,  and  lungs ;  broncho-pneu- 
monia;   colon;   chronic  interacinar  pancreatitis  (slight). 

Macroscopically  the  pancreas  appeared  unchanged,  but  micro- 
scopic examination  showed  the  occurrence  of  thickened  strands  of 
connective  tissue  between  the  acini.  The  increase  of  interstitial 
tissue  is,  however,  slight,  and  in  many  places  is  entirely  absent. 
Only  rarely  are  the  islands  of  Langerhans  implicated  in  the  chronic 
inflammatory  process. 

Of  nine  cases  of  chronic  interacinar  pancreatitis, 
seven  were  accompanied  by  diabetes  mellitus.  In 
those  in  which  diabetes  was  absent — namely,  in  the 
case  with  hsemochromatosis  and  in  Case  XXIV.,  just 
described — the  lesion  was  little  advanced  and  the 
islands  of  Langerhans  were  only  slightly  affected. 
The  significance  of  these  facts  will  be  considered  in 
the  pages  to  follow. 

The  data  contained  in  the  present  chapter  may  be 
briefly  summarized  in  the  following  conclusions  : 

Chronic  interstitial  pancreatitis  is  slightly  more  fre- 
quent in  males  than  in  females.  The  disease  is  rare  in 
early  life,  and  two-thirds  of  the  total  number  of  cases 
occur  between  the  ages  of  forty  and  sixty  years. 


ETIOLOGY    OF   CHRONIC    PANCREATITIS.         213 

The  most  frequent  cause  of  chronic  pancreatitis  is 
obstruction  of  the  duct  of  Wirsung,  due  to  pancreatic 
calculi,  to  biliary  calculi  in  the  terminal  part  of  the 
common  bile  duct,  or  to  carcinoma  invading  the  head 
or  body  of  the  gland.  Obstruction  of  the  duct  may  be 
followed  by  the  invasion  of  bacteria,  and  these  take 
part  in  the  production  of  the  resulting  lesion. 

Ascending  infection  of  the  unobstructed  duct  of 
Wirsung  may  follow  an  acute  lesion  of  the  duodenum 
or  of  the  bile  passages,  and  may  cause  chronic  inflam- 
mation. In  cases  which  have  given  a  history  of  long- 
persistent  vomiting,  chronic  profuse  pancreatitis  may- 
be found  at  autopsy,  and  is  probably  the  result  of  an 
ascending  infection  of  the  gland. 

Following  obstruction  of  the  ducts  and  ascending 
infection,  the  lesion  of  chronic  interlobular  pancreatitis 
affects  principally  the  interlobular  tissue,  only  secon- 
darily invades  the  lobules,  and  spares  the  islands  01 
Langerhans. 

Accompanying  the  so-called  atrophic  or  Laennec's 
cirrhosis  of  the  liver,  the  pancreas  is  at  times  the  seat 
of  a  diffuse  chronic  inflammation,  chronic  interacinar 
pancreatitis,  characterized  by  proliferation  of  the  in- 
teracinar tissue  which  invades  the  islands  of  Langer- 
hans. A  similar  lesion  accompanies  arterial  sclerosis, 
hyaline  degeneration  of  the  islands  of  Langerhans,  and 
the  condition  known  as  haemochromatosis. 


CHAPTER    IX. 

HYALINE    DEGENERATION    OF    THE    PANCREAS. 

The  lesions  of  the  pancreas  previously  described  do 
not  exhibit  a  tendency  to  attack  and  destroy  the  islands 
of  Langerhans,  leaving  uninjured  the  secreting  paren- 
chyma. The  cells  of  the  interacinar  islands  often  contain 
fat  in  much  larger  quantity  than  those  of  the  secreting 
acini,  but  accumulation  of  fat  occurs  with  such  frequency 
that  it  may  be  regarded  as  a  physiological  process. 
With  the  interacinar  type  of  chronic  interstitial  pan- 
creatitis the  islands  of  Langerhans  are  invaded,  but  the 
remaining  glandular  parenchyma  is  almost  equally 
affected.  One  form  of  degeneration,  however,  exhibits 
a  specific  tendency  to  select  and  destroy  the  interacinar 
islands,  though  in  most  cases  it  leaves  the  secreting 
parenchyma  almost  unaffected. 

In  a  considerable  number  of  cases  recently  observed 
the  pancreas  has  been  found  to  be  the  seat  of  a  peculiar 
hyaline  change  which  destroys  the  islands  of  Langer- 
hans. The  association  of  diabetes  mellitus  with  the 
lesion  has  given  much  interest  to  its  study.  This 
peculiar  transformation  affecting  the  islands  of  Langer- 
hans belongs  to  the  varied  and  ill-defined  group  of 
degenerative  processes  of  which  the  common  charac- 
teristic is  the  formation  of  a  homogeneous  or  hyaline 
214 


HYALINE   DEGENERATION. 


215 


material.  This  substance  stains  with  acid  dyes,  such 
as  eosin  and  picric  acid,  but  does  not  give  the  reactions 
of  amyloid,  though  it  resists  the  action  of  a  variety  of 
solvents,  for  example,  strong  acids  and  alkalies.  These 
characteristics  have  been  used  by  von  Recklinghausen 
to  group  together  products  of  cell  degeneration  occur- 
ring in  widely  different  tissues  and  doubtless  represent- 
ing a  variety  of  essentially  different  processes,  which 
even  yet  have  received  no  satisfactory  classification. 

Several  years  ago  I  had  the  opportunity  of  studying 
the  pancreas  from  a  girl  who  for  two  years  before  her 
death  had  suffered  with  diabetes  mellitus.  The  organ 
was  the  seat  of  a  lesion  which  obliterated  the  vascular 
supply  of  a  considerable  proportion  of  the  parenchyma. 
The  process  which  has  the  character  of  hyaline  de- 
p-eneration,  thouorh  not  confined  to  the  islands  of 
Langerhans,  has  so  completely  altered  them  that  they 
are  not  recognizable.  The  lesion  is  so  remarkable  and 
its  association  with  diabetes  of  such  interest  that  the 
following  details  are  given  : 

Case  XXV. — .The  patient,  a  girl,  aged  seventeen  years,  was  in  the 
care  of  Dr.  James  Carey  Thomas.  The  onset  of  symptoms  of  the 
fatal  illness  occurred  two  years  before  death  with  extreme  thirst  and 
polyuria ;  sugar  was  found  in  the  urine  and  was  constantly  present  in 
large  amount  until  death.  Upon  diabetic  diet  the  sugar  diminished 
in  amount  but  did  not  disappear.  Marked  loss  of  body-weight  was 
not  noted.  Death  occurred  with  coma,  which  appeared  suddenly  and 
lasted  hardly  more  than  twenty-four  hours.  At  autopsy  the  only 
lesion  noted  was  that  affecting  the  pancreas ;   the  entire  organ  was 


2i6  DISEASE    OF   THE    PANCREAS. 

presen-ed  for  microscopic  study   and  kindly  given  to    me   by    Dr. 
Flexner,  who  performed  the  autopsy. 

Microscopic  Examination  of  the  Pancreas. — The  organ  is  in  large 
part  self-digested.  In  the  tail,  however,  several  areas  where  the 
tissue  is  well  preserved  give  a  clear  histological  picture  of  the  lesions 
which  are  present.  The  interstitial  tissue  is  increased  only  in  several 
small  areas.  Throughout  the  organ,  readily  distinguishable  even 
in  the  most  digested  parts  of  the  gland,  are  very  conspicuous, 
sharply  defined,  round  or  oval,  hyaline  areas  embedded  in  the  paren- 
chyma ;  they  vary  considerably  in  size.  Though  the  parenchyma- 
tous cells  stain  with  haematoxylin,  these  areas  stand  out  conspicuously 
as  almost  completely  unstained  foci.  Their  structure  is  as  follows 
(see  Fig.  i8)  :  Coarse,  tortuous,  hyaline  columns  separate  strands  of 
tissue,  which  contain  nuclei  and  represent,  in  part  at  least,  capillary 
endothelium,  from  compressed  rows  of  epithelial  cells, — evidently 
atrophied  parenchymatous  cells.  The  hyaline  material  lies  im- 
mediately outside  the  capillary  wall,  betAveen  capillary  and  adjacent 
epithelial  cells.  Occasionally  the  lumen  of  the  capillary  is  visible 
and  may  contain  shadows  of  red  corpuscles. 

Epithelial  cells  between  the  tortuous  hyaline  columns  form  com- 
pressed rows  varying  in  width.  The  cells  which  are  diminished  in 
size  are  usually  arranged  in  columns.  Rarely  within  the  area  of 
hyaline  change,  most  frequently  in  its  periphery,  are  cells  grouped 
about  a  well-marked  lumen.  Islands  of  Langerhans  are  not  recog- 
nizable. The  hyaline  material  does  not  stain  by  Weigert's  method 
for  the  staining  of  fibrin.  Reactions  for  amyloid  are  not  obtained 
with  specimens  hardened  in  alcohol. 

Microscopic  Examination  of  other  Organs. — The  liver  is  normal  in 
appearance ;  there  is  no  increase  of  interstitial  tissue  and  the  blood- 
vessels are  normal.  In  a  section  from  the  kidney  a  small  collection 
of  lymphoid  cells  is  present  at  one  point.  Otherwise  no  change  is 
noted. 


r4^"*^''VjJ^^ 


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2f  s>     <s 


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Fig.  i8. — Hyaline  degeneration  of  the  pancreas.     (Case  XXV.) 


HYALINE    DEGENERATION.  217 

The  very  remarkable  lesion  just  described  has  ap- 
parendy  obstructed  the  vascular  supply  of  a  large 
proportion  of  the  pancreatic  parenchyma.  Newly- 
formed  hyaline  material  is  deposited  between  the  capil- 
laries and  the  parenchymatous  cells  (see  Fig.  18).  The 
tissue  studied  having  been  hardened  in  ninety-five  per 
cent,  alcohol,  the  absence  of  reactions  for  amyloid  is 
not  conclusive.  That  the  lesion  is  not  this  form  of 
degeneration  is  shown  by  the  absence  of  similar  change 
in  other  organs  which  much  more  frequently  than  the 
pancreas  are  the  seat  of  amyloid  degeneration. 

In  the  tail  of  the  pancreas  areas  of  hyaline  trans- 
formation are  larger  and  more  numerous  than  else- 
where, involving  at  least  two-thirds  of  the  sectional  area. 
Though  the  remainder  of  the  parenchyma  is  in  a  fair 
state  of  preservation,  islands  of  Langerhans  are  not 
found.  The  absence  of  recognizable  islands  of  Lang- 
erhans in  the  tail  is  especially  remarkable  when  we 
remember  that  they  are  normally  most  abundant  in  this 
part  of  the  organ.  It  is  evident,  therefore,  that  the 
lesion  has  implicated  these  structures  ;  but  that  it  is  not 
confined  to  them  in  shown  by  the  extent  and  abundance 
of  the  affected  areas.  Often  the  latter  correspond  in 
size  and  shape  to  the  islands,  but  they  may  be  several 
times  as  large.  Moreover,  the  occurrence  of  epithelial 
cells  arranged  about  a  lumen,  particularly  at  the  pe- 
riphery of  the  altered  tissue,  shows  that  acini  as  well  as 
interacinar  islets  are  affected.     In  the  head  and  body  of 


21 8  DISEASE    OF   THE    PANCREAS. 

the  gland,  areas  of  hyaline  transformation  are  less 
abundant  and  smaller,  usually  corresponding  in  size 
to  islands  of  Langerhans.  Unfortunately,  self-digestion 
of  these  parts  of  the  organ  prevents  the  recognition 
of  very  early  stages  of  the  lesion  and  of  their  relation 
to  the  various  histological  elements. 

Rokitansky  states  that  the  pancreas  is  not  infrequently 
the  seat  of  amyloid  degeneration,  caused  by  the  usual 
etiological  factors  and  associated  with  the  presence  of 
the  lesion  in  other  organs.  Sometimes  degenerative 
changes,  he  thinks,  are  limited  to  the  gland.  The 
possibility  suggests  itself  that  he  observed  a  lesion 
similar  to  the  one  described  ;  this  lesion  has  many  of 
the  characters  of  amyloid  degeneration  though  the 
specific  reactions  are  not  obtainable,  Saunby  has  de- 
scribed a  condition  of  hyaline  degeneration  affecting 
the  secreting  parenchyma  of  the  pancreas  and  associ- 
ated with  diabetes.  The  altered  tissue  is  converted 
into  swollen  convoluted  masses  of  transparent  material 
containing  a  few  pale  nuclei.  He  thinks  that  the  se- 
creting cells  undergo  a  process  resembling  the  gly- 
cogenic degeneration  of  the  kidneys  and  at  the  same 
time  the  fibrous  interstitial  tissue  increases  in  amount. 

Hyalme  Degeneration  of  the  Islands  of  Langerhans. — 
In  a  second  case  of  diabetes  the  localization  of  hyaline 
changes  in  the  islands  of  Langerhans  has  been  clearly 
demonstrated ;  these  bodies  are  the  seat  of  a  degener- 
ative change  which  has  left  almost  unaltered  the  secret- 


HYALINE    DEGENERATION. 


219 


ing  parenchyma  of  the  gland.  I  have  made  a  report  of 
this  case  in  the  yournal  of  Experimental  Medicine.  It 
is  here  quoted  in  considerable  detail,  because  the  lesion, 
previously  undescribed,  demonstrates  very  clearly,  as 
will  be  shown  later,  the  relationship  of  diabetes  mel- 
litus  to  the  islands  of  Langerhans. 

Case  XXVI. — The  patient,  a  negro  woman,  aged  fifty-four  years, 
was  admitted  to  the  Johns  Hopkins  Hospital,  in  the  service  of  Dr. 
Osier,  complaining  of  cough.  Her  present  illness  began  about 
eleven  months  before  her  admission,  when,  she  stated,  she  had  a 
severe  cold  which  became  steadily  worse.  She  had  lost  much  weight. 
Several  months  after  the  onset  of  cough  her  urine  increased  greatly 
in  quantity,  so  that  for  a  time  she  was  compelled  to  get  up  almost 
every  hour  during  the  night  to  void  it.  At  this  time  she  experi- 
enced great  hunger  and  thirst,  and  ate  and  drank  enormously. 
These  symptoms  lasted  during  part  of  the  spring  and  summer,  and 
disappeared  some  months  before  her  admission  to  the  hospital.  She 
had  recently  voided  the  usual  amount  of  urine,  and  there  was  no 
excessive  hunger  or  thirst. 

When  admitted  the  patient  was  thin  but  moderately  well  nour- 
ished. Signs  of  consolidation  were  found  at  the  apices  of  both  lungs, 
and  tubercle  bacilli  were  demonstrated  in  the  sputum.  The  stools 
were  of  normal  color  and  contained  no  fat.  The  patient  gradually 
became  weaker.  The  temperature  was  irregular.  Death  occurred 
on  the  seventh  day  after  admission,  and  was  not  preceded  by  a 
period  of  coma. 

The  specific  gravity  of  the  urine  varied  between  1025  and  1035. 
It  contained  sugar  in  abundance  ;  neither  albumen  nor  casts  were 
found.  On  the  fourth  day  after  admission  eight  hundred  and  eighty 
cubic  centimetres  were  collected ;  the  specific  gravity  was  1028,  and 
four  per  cent,   of  sugar  was  present.      On   the   following   day  the 


2  20  DISEASE    OF    THE    PANCREAS. 

amount  was  twelve  hundred  cubic  centimetres,  the  specific  gravity 
1035,  and  the  quantity  of  sugar  5.4  per  cent. 

Autopsy. — The  body  is  that  of  a  sparely  nourished  woman.  Sub- 
cutaneous fat  is  present  in  small  amount.  The  heart  is  normal  in 
appearance  ;  within  the  coronary  arteries  near  their  orifices  are  a 
few  slightly  raised,  yellow  patches.  Occupying  the  upper  part  of 
the  upper  lobe  of  the  left  lung  is  a  large,  irregular  cavity,  the 
walls  of  which  are  covered  by  yellowish  necrotic  material.  The  re- 
mainder of  the  lobe  is  consolidated,  and  riddled  with  small  cavities. 
The  upper  part  of  the  lower  lobe  is  very  thickly  studded  with  groups 
of  confluent,  partly  caseous  tubercles.  At  the  apex  of  the  right 
lung,  below  the  pleura,  is  a  cavity,  which  in  size  and  appearance 
resembles  that  of  the  left  lung. 

The  liver  is  pale,  and  upon  the  cut  surface  are  seen  rather  con- 
spicuous yellowish  tubercles  of  minute  size.  The  spleen  is  not  en- 
larged. The  kidneys  are  of  large  size,  and  weigh  together  four  hun- 
dred grammes.  The  surface,  after  removal  of  the  capsule,  is  smooth 
and  pale.  In  the  lower  part  of  the  ileum  are  a  few  scattered  super- 
ficial ulcers,  with  irregular,  slightly  raised  edges.  A  few  similar 
ulcers  are  present  in  the  large  intestine. 

The  pancreas,  which  weighs  eighty  grammes,  can  be  readily  dis- 
sected from  the  surrounding  tissues.  It  is  soft  in  consistence,  on 
section  has  a  grayish-yellow  color,  and  appears  to  be  normal. 

The  intima  of  the  aorta,  though  fairly  smooth,  is  studded  with 
irregular,  slightly-raised  plaques.  The  arteries  at  the  base  of  the 
brain  are  normal  in  appearance.  No  lesion  of  the  brain  is  found  ; 
the  floor  of  the  fourth  ventricle  presents  nothing  unusual. 

Histological  Characters  of  the  Hyaline  Islands  oj 
LangerJians. — In  sections  prepared  for  histological 
study  from  the  pancreas  of  the  case  just  described,  is 
found  no  generalized  increase  of  the  interstitial  tissue, 


^a^i- 


Fig.  19. — T>ra\ving:  made  with  Inw  mafrnification,  showing  hyaline  transformation  of  the  islands 

of  Lang;erhans. 


,<    \^l 


■^ 


•» 


Fir;.  20. — Drawing  made  with  a  higher  magnification,  showing  an  island,  cells  of  which  are  parlU 
transformed  into  hyaline  material. 


HYALINE    DEGENERATION.  221 

but  here  and  there,  particularly  in  the  tail  of  the  organ, 
the  fibrous  stroma  shows  some  proliferation,  and  there 
are  irregularly  distributed  strands  of  tissue  between  the 
acini.  This  scanty  newly-formed  interstitial  tissue, 
where  it  occurs,  is  poor  in  cells,  but  about  some  of  the 
medium-sized  interlobular  blood-vessels  are  small  accu- 
mulations of  scattered  lymphoid  cells,  together  with  an 
occasional  plasma  cell.  The  ducts  are  not  dilated  and 
appear  to  be  normal.  There  are  no  alterations  of  the 
veins  or  arteries. 

The  islands  of  Langerhans  are  the  seat  of  a  very 
remarkable  change  (see  Fig.  19).  In  varying  amount 
within  almost  every  island  is  a  homogeneous  material 
which  stains  with  eosin.  Only  rarely  is  found  an  un- 
altered island.  Those  which  are  least  changed  contain 
a  few  scattered  masses  of  hyaline  material,  of  which  the 
smallest  are  irregularly  polygonal  in  shape  and  corre- 
spond in  size  to  the  cells  of  the  island  ;  the  larger  par- 
ticles are  rounded.  This  hyaline  substance  lies  at 
times  in  the  midst  of  groups  of  cells,  but  is  usually  in 
contact  with  the  capillaries  of  the  island,  or  next  the 
peripheral  fibrous  tissue,  and  is  therefore  between  the 
remaining  cells  and  the  capillary  walls.  Increasing  in 
amount,  it  replaces  the  cells  and,  where  it  is  abundant, 
the  cells  which  still  persist  are  small  and  contain  small 
nuclei,  staining  deeply  with  haematoxylin  ;  but  they  do 
not  appear  compressed  or  distorted. 

In  islands  of  Langerhans,  where  the  lesion  is  more 


22  2  DISEASE    OF   THE    PANCREAS. 

advanced,  hyaline  material  occurs  as  conspicuous  masses 
in  contact  with  capillaries,  the  endothelium  of  which  is 
well  preserved.  It  does  not  form  a  uniform  zone  about 
them,  but  occurs  as  scattered  groups  of  irregular, 
rounded,  often  globular  masses  (see  Fig.  19).  The 
cells  of  the  island  have  been  in  large  part  replaced,  and 
between  the  hyaline  particles  is  seen  only  an  occasional 
compressed,  fusiform,  or  irregular  nucleus. 

The  hyaline  substance  may  occupy  almost  the  entire 
area  of  the  island,  and  besides  a  few  endothelial  cells 
are  found  only  small  scattered  groups  or  rows  of  atro- 
phic epithelial  cells.  The  island  is  represented  by  a 
sharply  circumscribed  hyaline  structure,  composed  ot 
particles  of  homogeneous  material,  giving  the  impres- 
sion of  broken,  twisted  columns,  between  which  are 
capillary  walls.  The  nuclei  of  the  capillary  endothe- 
lium persist  after  destruction  of  the  epithelial  cells,  but 
finally  disappear.  The  lumen  of  the  capillary  remains 
patent,  and  red  blood-corpuscles  are  seen  between  the 
hyaline  masses,  although  the  endothehum  no  longer 
contains  nuclei.  Hyaline  metamorphosis  is  limited 
strictly  to  the  islands  of  Langerhans,  the  glandular 
acini  remaining  intact. 

Lesions  similar  to  those  of  the  pancreas  are  not 
present  in  other  organs.  The  blood-vessels  of  the 
liver,  spleen,  and  kidney  are  apparently  unaltered, 
and  there  is  no  formation  of  hyaline  material  in  these 
organs. 


HYALINE   DEGENERATION.  223 

Additional  Cases  of  Hyaline  Degeneration  Affecting 
the  Islands  of  Langerhans. — The  peculiarly  localized 
lesion  observed  in  the  preceding  cases  of  diabetes 
demonstrates,  I  believe,  a  casual  relationship  between 
alterations  of  the  islands  of  Langerhans  and  the  dis- 
ease diabetes  mellitus.  This  relationship  will  be  dis- 
cussed in  a  later  chapter.  Confirmation  was  afforded 
by  the  occurrence  of  the  same  lesion  in  two  cases  of 
diabetes  which  subsequently  came  to  autopsy  in  the 
pathological  laboratory  of  the  Johns  Hopkins  Hospital. 
Since  this  characteristic  lesion  had  not  been  described, 
its  occurrence  was  at  first  thought  to  be  rare.  In  addi- 
tion to  these  cases,  however,  other  observers  studying 
the  pathology  of  diabetes  have  recently  noted  similar 
changes,  so  that  the  association  of  the  two  conditions 
cannot  be  regarded  as  uncommon. 

In  the  two  cases  to  follow  the  islands  of  Langerhans 
were  the  seat  of  destructive  changes  comparable  to 
those  present  in  Case  XXVI. 

Case  XXVII. — The  patient,  male,  colored,  aged  forty-eight 
years,  was  admitted  to  the  Johns  Hopkins  Hospital  in  order  that 
an  operation  for  cataract  might  be  performed.  For  six  or  seven 
years  he  had  been  troubled  with  dimness  of  vision.  No  evidence  of 
syphilis  nor  of  alcoholic  excess  was  obtainable.  The  patient  had 
suffered  for  several  months  with  nausea  and  vomiting  in  the  early 
morning.  Shortly  after  the  operation  the  patient  became  comatose. 
Sugar  was  present  in  the  urine,  constituting  four  per  cent.  ;  acetone 
and  diacetic  acid  were  found.  The  patient  died  at  the  end  of  two 
days. 


224 


DISEASE    OF   THE    PANCREAS. 


Anatomical  Diagnosis. — Hyaline  degeneration  of  the  pancreas 
affecting  the  islands  of  Langerhans.  Hypertrophy  of  the  kidneys 
with  slight  chronic  diffuse  nephritis.  Chronic  catarrhal  gastritis. 
(Edema  of  lungs. 

The  pancreas  weighs  61.5  grammes.  The  substance  is  flaccid  and 
appears  to  be  normal,  being  nowhere  indurated  and  not  abnormally 
adherent  to  the  adjacent  structures. 

Microscopic  examination  of  the  pancreas  shows  a  slight  increase 
of  the  interacinar  connective  tissue,  though  in  many  places,  particu- 
larly in  the  head  of  the  gland,  the  interstitial  tissue  is  normal. 
Throughout  the  organ  islands  of  Langerhans  exhibit  almost  uni- 
versally, but  in  varying  degree,  the  hyaline  change  already  described. 
Islands  of  Langerhans  are  very  numerous  in  the  tail,  and  here  hyaline 
degeneration  is  very  conspicuous.  Where  epithelial  cells  are  almost 
wholly  replaced,  the  hyaline  substance  has  acquired  a  very  homo- 
geneous appearance  and  forms  globular  masses,  which  are  pressed 
together  to  form  tortuous  columns  lying  beside  the  capillary  vessels 
or  in  contact  with  the  connective-tissue  capsule  of  the  island. 

Case  XXVIII. — The  patient,  male,  seventy-three  years  of  age, 
was  admitted  to  the  service  of  Dr.  Osier  complaining  of  weakness 
and  stiffness  of  the  legs.  There  was  no  history  of  syphilis  nor  of 
alcoholic  excess.  None  of  the  usual  symptoms  of  diabetes  had  been 
noted.  About  ten  months  before  his  death,  when  first  admitted  to 
the  hospital,  sugar  was  found  in  the  urine  varying  from  1.9  to  4.5 
per  cent.,  the  total  amount  excreted  in  twenty-four  hours  being  29 
to  49.3  grammes.  When  given  a  diet  free  from  carbohydrates  sugar 
disappeared  from  the  urine.  The  patient  was  again  admitted  to  the 
hospital  about  nineteen  days  before  death.  Signs  of  pulmonary 
tuberculosis  were  present,  and  in  the  sputum  tubercle  bacilli  were 
found.  The  urine  contained  3.6  per  cent,  sugar,  but  shortly  before 
death  glycosuria  disappeared. 

Anatomical  Diagnosis. — Hyaline  degeneration  of  the  islands  of 


HYALINE    DEGENERATION.  225 

Langerhans  with  chronic  interacinar  pancreatitis.  Puhnonary  tuber- 
culosis with  cavity  formation.  Chronic  diffuse  nephritis  ;  large  red 
kidneys.  Thrombosis  of  the  left  femoral  and  common  iliac  veins ; 
thrombosis  of  the  left  pulmonary  artery.  General  arterial  sclerosis ; 
mural  thrombi  within  aorta.  Aberrant  pancreas  in  the  wall  of  the 
stomach. 

The  pancreas,  weighing  one  hundred  and  twenty  grammes,  is  firm 
in  consistence,  and  fat  is  abundant  between  the  lobules.  Near  the 
pyloric  orifice  of  the  stomach  is  a  small  nodule  of  pancreatic  tissue 
situated  in  the  submucosa  and  muscularis  (described  in  Chapter  II. ) . 

Microscopic  examination  shows  that  fat  is  abundant  in  the  inter- 
stitial tissue  of  the  pancreas,  penetrating  in  many  places  between  the 
acini.  Throughout  the  organ  there  is  a  moderate  irregularly  dis- 
tributed increase  of  the  interstitial  tissue  between  the  acini.  Islands 
of  Langerhans  are  abundant  in  all  parts  of  the  gland,  and  are  the 
seat  of  hyaline  degeneration  similar  to  that  already  described.  In 
the  head  and  body  of  the  organ  occur  islands  that  appear  to  be 
normal,  but  in  the  tail,  where  these  structures  are  most  numerous, 
they  are  almost  universally  altered.  The  change  in  many  instances 
is  so  far  advanced  that  the  epithelial  cells  are  almost  completely 
replaced  by  hyaline  substance. 

In  the  following  case  diabetes  was  of  mild  type,  and 
g-lycosuria  disappeared  when  the  patient  was  given  a 
diet  poor  in  carbohydrates.  Changes  in  the  pancreas, 
though  present,  were  less  extensive  than  in  the  pre- 
ceding cases,  and  only  a  few  islands  of  Langerhans 
were  the  seat  of  advanced  hyaline  changes. 

Case  XXIX. — The  patient,  male,  white,  aged  fifty-one  years, 
denies  venereal  disease  ;  he  has  been  in  the  habit  of  drinking  daily 
several  pints  of  beer  and   sour  wine.     The   present    illness   began 

15 


226  DISEASE    OF   THE    PANCREAS. 

with  a  cough  about  a  year  and  a  half  before  its  fatal  termination  ; 
expectoration  was  abundant  and  tubercle  bacilli  were  found  in  the 
sputum.  When  first  admitted  to  the  service  of  Dr.  Osier  the  urine 
contained  from  seven  to  eight  per  cent,  of  sugar,  but  with  rest  in 
bed  and  a  diet  free  from  carbohydrates  glycosuria  disappeared.  On 
two  subsequent  occasions  the  patient  returned  to  the  hospital,  and 
upon  similar  treatment  sugar,  present  to  the  amount  of  from  three 
to  six  per  cent,  on  admission,  disappeared  from  the  urine. 

Anatomical  Diagnosis. — Hyaline  degeneration  of  the  islands  of 
Langerhans  with  chronic  interacinar  pancreatitis.  Chronic  pulmo- 
nary tuberculosis  with  cavity  formation.  General  arterial  sclerosis ; 
fatty  degeneration  of  the  heart.  Chronic  diffuse  nephritis.  Focal 
necrosis  of  the  liver. 

The  pancreas,  which  weighs  sixty-five  grammes,  is  fairly  firm  in 
consistence.  The  splenic  artery  is  thickened  and  tortuous  and  its 
intima  shows  raised  sclerotic  plaques. 

In  sections  for  microscopic  examination  from  all  parts  of  the 
pancreas,  but  most  marked  in  the  tail,  there  is  a  diffuse,  irregularly 
distributed  increase  of  the  interacinar  stroma.  Islands  of  Langer- 
hans are  fairly  abundant,  and  in  the  majority  of  instances  show  no 
alteration.  Occasionally  they  are  surrounded  and  penetrated  by 
thickened  strands  of  connective  tissue.  In  the  tail  are  found  inter- 
acinar islands  which  contain  hyaline  material,  while  in  several 
instances  almost  complete  hyaline  transformation  has  occurred. 

In  the  following  case  only  a  small  bit  of  pancreatic 
tissue  was  preserved.  As  in  the  preceding  case  hya- 
line degeneration  of  slight  extent  was  associated  with 
chronic  interacinar  inflammation.  It  is  not  improbable 
that  had  a  thorough  examination  been  possible  more 
marked    changes  would  have    been  found,   for    in  the 


HYALINE    DEGENERATION.  227 

cases  just  cited  interacinar  islands  in  the  tail  of  the 
gland  showed  most  marked  alterations.  The  severity 
of  the  diabetes  present  could  not  be  determined. 

Case  XXX. — The  patient,  male,  white,  aged  forty-seven  years, 
was  admitted  to  the  service  of  Dr.  Osier  four  days  before  death, 
complaining  of  weakness  and  loss  of  flesh.  Symptoms  of  diabetes 
had  been  present  six  months,  and  the  body-weight  had  diminished 
from  one  hundred  and  sixty-five  to  one  hundred  and  twenty-five 
pounds.  While  in  the  hospital  the  urine  contained  3.5  to  3.75  per 
cent,  of  sugar.      Death  occurred  with  coma. 

Anatomical  Diagnosis. — Chronic  interacinar  pancreatitis  with  hya- 
line degeneration  of  the  islands  of  Langerhans.  Emphysema  of 
lungs.     Fatty  degeneration  of  heart,  liver,  and  kidneys. 

The  pancreas  weighs  ninety  grammes,  and  on  gross  examination 
shows  no  abnormality.  On  microscopic  examination  is  found  mod- 
erate, irregularly  distributed  increase  of  the  interacinar  tissue. 
Islands  of  Langerhans  are  numerous,  and  the  greater  number  ap- 
pear to  be  unaltered,  but  a  few  are  surrounded  by  thickened  fibrous 
tissue,  while  others  contain  in  moderate  amount  the  hyaline  material 
observed  in  previous  cases. 

Since  the  publication  of  Case  XXVI.,  hyaline  degen- 
eration of  the  islands  of  Langerhans  accompanying  dia- 
betes has  been  observed  by  several  writers.  Wright 
and  Joslin  have  described  the  lesion  which  was  present 
in  two  cases.  The  first  patient,  aged  fifty  years,  had 
suffered  with  diabetes  two  and  a  half  years.  He  died 
in  coma  with  general  pyogenic  infection.  The  pan- 
creas was  the  seat  of  hyaline  degeneration  affecting 
the  islands  of  Langerhans,  while  the  secreting  paren- 


2  28  DISEASE    OF   THE    PANCREAS. 

chyma  showed  no  noteworthy  change.  The  second  case 
was  in  a  woman,  aged  fifty-eight  years,  who  was  treated 
for  diabetes  and  died  with  coma.  In  the  islands  of 
Langerhans  were  hyaHne  changes  ;  the  interstitial  con- 
nective tissue  was  increased  and  contained  much  fat. 

In  one  of  five  cases  of  diabetes  Herzog  found  hya- 
line degeneration  of  the  islands  of  Langerhans  accom- 
panied by  a  moderate  increase  of  the  interstitial  tissue. 
Schmidt  found  a  similar  lesion  accompanying  diabetes 
in  a  woman  sixty-two  years  of  age.  The  change  was 
unassociated  with  other  histological  alterations  of  the 
pancreas.  Weichselbaum  and  Stangl  have  doubtless 
observed  the  same  lesion,  though  they  do  not  describe 
it  in  sufficient  detail  to  identify  it  with  certainty. 

The  cases  already  cited  throw  little  light  upon  the 
etiology  of  the  lesion.  It  appears  to  be  equally  com- 
mon in  males  and  in  females,  and  of  nine  cases  de- 
scribed with  sex  and  age  (six  herewith  described,  two 
of  Wright  and  Joslin  and  one  of  Schmidt),  five  were 
male  and  four  female.  One  case  (Case  XXV.)  was  a 
girl  seventeen  years  of  age,  but  the  remainder  occurred 
after  middle  life  :  forty  to  fifty  years,  two  cases  ;  fifty 
to  sixty  years,  four  cases  ;  sixty  to  seventy  years,  one 
case  ;  and  seventy  to  eighty  years,  one  case.  In  two 
of  my  cases  the  condition  was  associated  with  marked 
arterial  sclerosis,  but  in  other  instances  the  blood- 
vessels showed  no  noteworthy  changes. 

In  most  cases  chronic  interstitial  pancreatitis  of  the 


HYALINE   DEGENERATION.  229 

interacinar  type  has  accompanied  the  lesion.  In  Cases 
XXYI.  and  XXVII.  inflammatory  changes  are  so  in- 
significant that  they  are  recognizable  only  in  certain 
parts  of  the  gland.  In  one  case  of  Wright  and  Joslin 
and  in  the  case  cited  by  Schmidt  none  were  observed. 
The  relationship  of  hyaline  degeneration  of  the  intera- 
cinar islands  to  interstitial  changes  occurring  in  the 
secreting  parenchyma  is  doubtful.  Since  large  readily 
injected  capillaries  enter  the  islands  of  Langerhans,  and 
subsequently  anastomose  freely  with  capillary  vessels  of 
the  surrounding  acini,  it  is  possible,  though  not  demon- 
strable, that  interference  with  the  circulation  in  the 
interacinar  islands  may  disturb  the  nutrition  of  the  sur- 
rounding parenchyma.  On  the  other  hand,  it  is  not 
improbable  that  both  processes  are  the  result  of  an 
irritant  carried  to  the  pancreas  by  the  blood.  In  Case 
XXV.,  though  the  lesion  has  destroyed  the  islands  of 
Langerhans,  it  has  overstepped  their  limits  and  impli- 
cates in  wide-spread  destruction  the  secreting  paren- 
chyma as  well.  In  the  remaining  cases,  however,  the 
hyaline  change  exhibits  a  remarkable  tendency  to 
sharply  limit  itself  to  the  interacinar  islands. 

Nature  of  the  Degenerative  Process. — Under  the 
heading  of  colloid  transformation,  von  Recklinghausen 
has  included  amyloid,  hyaline,  and  mucous  degenera- 
tion,— processes  of  which  the  common  character  is  a 
formation  of  substances  insoluble  in  the  tissue  juices. 
He  recognized   that  the  chemical  and  physical  peculi- 


230  DISEASE    OF    THE    PANCREAS. 

arities   ascribed   to    hyaline   material   do   not   serve   to 
identify  it  as  a  true  chemical  compound. 

Klebs  has  attempted  to  classify  more  precisely  these 
heterogeneous  processes,  and  to  define  more  clearly 
certain  long-accepted  terms  which  have  been  applied 
to  them.  He  reserves  the  name  "colloid"  for  those 
albuminous  substances  which  resemble  the  colloid  of 
the  thyroid  gland  and,  like  it,  are  elaborated  by 
secreting  cells,  though  not  necessarily  preformed  within 
them.  As  "hyaline"  he  designated  the  firm,  refrac- 
tive, and  homogeneous  albuminous  material  which  does 
not  give  the  reactions  of  amyloid,  and  is  formed  in  con- 
nective tissue  and  in  other  derivatives  of  the  meso- 
derm. 

By  means  of  staining  reactions,  P.  Ernst  has  at- 
tempted to  demonstrate  that  the  various  substances 
grouped  together  as  hyaline  are  not  chemically  iden- 
tical. Hyaline  material  from  different  sources,  when 
treated  with  Van  Gieson's  mixture,  exhibits  in  its 
affinity  for  acid  fuchsin  and  picric  acid  differences 
which  he  attributes  to  peculiarities  of  chemical  com- 
position. That  which  is  derived  from  epithelial  cells 
stains  orange-yellow  with  the  mixture  of  the  two  dyes, 
being  colored  by  the  picric  acid,  and  only  tinted  by 
fuchsin,  while  that  which  is  formed  in  connective  tissue 
is  stained  deep  red  by  fuchsin. 

Lubarsch  regards  the  staining  reactions  of  Ernst  as 
an   uncertain  means   for  the  identification  of  different 


HYALINE   DEGENERATION.  231 

hyaline  substances,  and  points  out  discrepancies  between 
the  criteria  proposed  by  Klebs  and  by  Ernst,  Although 
Lubarsch  discards  the  classification  of  Ernst,  he  admits 
that  the  method  employed  indicates  in  many  cases  the 
origin  of  hyaline  material.  Its  advantage,  he  believes, 
lies  in  the  fact  that  by  it  we  can  determine  if  the  par- 
ticular hyaline  substance  to  be  examined  contains  a 
constituent  derived  from  connective  tissue.  Normal 
fibrous  tissue  is  stained  intensely  red  by  acid  fuchsin, 
and  the  substances  upon  which  depend  its  affinity  for 
the  dye  are  present  in  the  degenerate  tissue.  Pure 
hyaline,  whatever  its  origin,  Lubarsch  suggests,  always 
stains  in  the  same  way,  while  differences  in  staining 
reaction  are  dependent  upon  the  admixture  of  other 
substances.  Following  Lubarsch,  we  may  distinguish 
hyaline  of  epithelial  origin  and  that  derived  from  con- 
nective tissue,  and,  again,  we  may  recognize  that  which, 
like  the  colloid  of  the  thyroid  gland,  is  formed  outside 
of  cells,  presumably  by  a  process  of  secretion,  and  that 
which  is  formed  by  transformation  of  the  cell  proto- 
plasm. 

The  material  which  in  the  cases  herewith  described 
partly  or  completely  replaces  the  islands  of  Langer- 
hans  was  tested  with  a  variety  of  agents  which  have 
been  used  in  the  study  of  hyaline  substances.  It  stains 
deeply  with  acid  dyes,  like  eosin  and  picric  acid,  but 
shows  little  affinity  for  nuclear  stains,  as,  for  example, 
hsematoxylin  and  methylene  blue. 


232  DISEASE    OF   THE    PANCREAS. 

The  reactions  of  amyloid  were  not  obtained  with 
iodine,  nor  with  gentian  violet,  methyl  violet,  nor  iodine 
green.  The  material  did  not  stain  by  Weigert's  method 
for  the  demonstration  of  fibrin. 

Of  much  interest,  in  view  of  the  study  of  Ernst,  is  the 
behavior  of  the  substance  towards  picric  acid  and  acid 
fuchsin.  It  stains  with  picric  acid,  but  shows  no  marked 
affinity  for  acid  fuchsin.  The  material,  therefore,  con- 
ducts itself  towards  Van  Gieson's  stain  as  does,  accord- 
ing to  Ernst,  hyaline  of  epithelial  origin. 

Finding  hyaline  substance  in  irregular  masses  in 
contact  with  the  cells,  I  was  at  first  inclined  to  believe 
that  it  was  formed  by  a  process  resembling  secretion. 
It  was  pointed  out  to  me  by  Dr.  Welch,  who  examined 
my  specimens,  that  transitions  occurred  between  the 
cells  and  the  hyaline  masses.  In  slightly  altered  islands 
one  finds  small  masses  of  material  which  resemble  the 
hyaline  substance,  but,  like  the  cell  protoplasm,  have  a 
granular  aspect.  They  correspond  in  size  to  the  adja- 
cent cells  of  the  island,  but  contain  no  nuclei. 

By  the  use  of  certain  stains,  phosphomolybdic  acid 
haematoxylin  by  the  method  of  Ribbert  for  white  fibrous 
tissue  or  aniline  blue  as  employed  by  Mallory  for  the 
demonstration  of  white  fibres  and  reticulum,  the  hyaline 
material  acquires  a  deep-blue  color  and  becomes  very 
conspicuous.  In  the  islands  of  Langerhans  are  not  in- 
frequently found  slightly  enlarged  cells,  which,  though 
still  containing  nuclei,  exhibit  a  reaction  similar  to  that 


HYALINE   DEGENERATION.  233 

of  the  hyaline  material  ;  the  cell  protoplasm,  which  is 
still  granular,  has  assumed  a  diffuse  blue  color. 

The  degenerative  process  first  manifests  itself  by  an 
increase  in  the  size  of  the  cell  and  an  alteration  of 
its  protoplasm.  With  the  death  of  the  cell  its  nucleus 
disappears,  and  the  protoplasm  which  stains  with  acid 
dyes  remains  for  a  time  granular,  but  subsequently  be- 
comes homogeneous.  Such  small  particles  of  hyaline 
fuse  with  one  another  and  form  largrer  masses  which  lie 
in  contact  with  the  fibrous  septa  of  the  island.  After 
complete  transformation  of  its  cells  the  island  is  repre- 
sented by  a  hyaline  mass  penetrated  by  the  remains  of 
altered  capillaries. 

Focal  Necrosis  of  the  Pancreas. — An  additional  case 
of  diabetes  has  been  associated  with  a  lesion  which 
differs  from  that  present  in  the  cases  already  cited.  A 
destructive  lesion  of  the  pancreas  affects  not  only  the 
interacinar  islands,  causing  death  of  their  cells,  but 
has  attacked  the  secreting  parenchyma  as  well.  The 
process  does  not  present  the  characters  of  hyaline 
degeneration  already  described,  but  occurring  in  foci 
closely  resembles  the  coagulative  necrosis  so  frequently 
observed  in  the  liver  in  association  with  typhoid  fever 
and  other  infections.  Cells  of  the  islands  of  Laneerhans 
and  of  the  acini  have  undero^one  necrosis,  but  there  is 
no  formation  of  compact  hyaline  material,  the  presence 
of  which  is  characteristic  of  the  lesions  previously  ob- 
served.     The  process  is  apparently  acute,  yet  through- 


234 


DISEASE    OF    THE    PANCREAS. 


out  the  gland  the  presence  of  beginning  chronic  inflam- 
matory changes  suggests  that  the  interstitial  tissue  may 
proliferate  in  order  to  replace  defects  caused  by  de- 
struction of  the  parenchymatous  cells. 

Case  XXXI. — W.  M.,  male,  colored,  aged  forty-eight  years,  was 
admitted  to  the  service  of  Dr.  Osier  complaining  of  frequent  mictu- 
rition, great  thirst,  and  hunger,  with  which  he  had  suffered  for  three 
months.  Two  months  previously  sugar  had  been  found  in  the  urine. 
He  had  a  cough,  and  his  weight  had  diminished  from  one  hundred 
and  sixty-six  to  one  hundred  and  ten  pounds.  Shortly  before  ad- 
mission to  the  hospital  he  suddenly  became  unconscious,  and  hemi- 
plegia affecting  the  left  side  appeared.  Death  occurred  on  the 
second  day  after  admission.  The  urine,  examined  twice,  contained 
from  three  and  a  half  to  seven  per  cent,  of  sugar. 

Anatomical  Diagnosis. — Pulmonary  tuberculosis  with  cavity  for- 
mation ;  acute  endocarditis  of  the  aortic  and  mitral  valves ;  in- 
farcts in  the  spleen  and  kidney ;   chronic  diffuse  nephritis. 

The  pancreas  presents  no  notable  abnormality ;  a  few  ecchy- 
moses  are  seen  upon  its  surface.  Microscopic  examination  shows  a 
slight  increase  of  the  interstitial  tissue  at  the  expense  of  the  paren- 
chyma. Newly-formed  connective  tissue,  which  occurs  in  irregular 
isolated  patches  within  the  lobules,  contains  few  cells,  and  is  dis- 
tended as  though  by  oedema.  Foci  of  necrosis  are  found  in  the  paren- 
chyma, and  involve  small  areas  consisting  of  a  considerable  number 
of  acini.  The  secreting  cells  have  here  lost  their  nuclei,  and  the 
cell  protoplasm  takes  a  bright  stain  with  eosin  ;  the  appearance  is  that 
of  coagulative  necrosis  in  the  liver.  Within  such  an  area  is  found 
in  many  instances  an  island  of  Langerhans  which  has  undergone  an 
analogous  change  ;  the  cells  have  lost  their  nuclei.  Rarely  the  cells 
of  an  island  have  undergone  necrosis  while  the  surrounding  acini 
are    entirely   normal.      Delicate   interstitial    tissue   is  in   process    of 


HYALINE    DEGENERATION. 


235 


formation  within  one  focus  of  necrosis,  and  it  is  not  improbable  that 
the  irregularly  distributed  increase  of  stroma  is  the  result  of  previous 
degenerative  changes.  A  few  normal  islands  of  Langerhans  are 
found,  but  throughout  the  gland  these  structures  are  very  sparsely 
scattered.  In  sections  from  the  head  of  the  gland  foci  of  necrosis 
are  not  found,  but  otherwise  the  tissue  resembles  that  of  the  body  ; 
tissue  from  the  splenic  extremity  was  not  preserved. 

The  process  occurring  in  the  preceding  case  presents 
features  which  differ  from  those  of  the  hyaUne  change 
previously  described.  The  pancreas  appears  to  be  the 
seat  of  focal  coaoulative  necrosis  similar  to  that  which 
attacks  the  liver  and  other  organs.  The  parenchyma- 
tous cells  are  not  converted  into  homogfeneous  masses 
of  hyaline  material,  but  preserving  their  identity  for  a 
time,  lose  their  nuclei  and  stain  deeply  with  eosin. 
The  possibility  suggests  itself  that  patches  of  deli- 
cate sclerosis  represent  previous  foci  of  similar  char- 
acter. Islands  of  Langerhans  are  implicated  in  the 
process,  and  their  number  is  much  less  than  that  usually 
found.  In  the  following  chapters  will  be  considered 
the  relationship  of  this  and  the  other  lesions  of  the 
islands  of  Langrerhans  to  diabetes  mellitus  with  which 
they  have  been  found  associated. 


CHAPTER    X. 

THE    PATHOLOGY    OF    DIABETES    MELLITUS. 

Before  considering  the  relationship  of  the  disease 
diabetes  mellitus  to  lesions  of  the  pancreas,  exemplified 
by  many  of  the  cases  previously  described,  it  is  desira- 
ble to  review  hastily  the  important  facts  which  concern 
this  important  disturbance  of  nutrition.  The  literature 
of  diabetes  mellitus  is  very  voluminous.  To  the  great 
clinical  importance  of  the  disease  is  added  the  interest 
which  attaches  to  its  bearing  upon  the  physiology  of 
carbohydrate  metabolism.  Nevertheless,  facts  which 
have  been  fully  established  are  few,  and  though  the 
condition  is  subject  to  varied  experimentation,  the  re- 
sults obtained  have  been  often  contradictory.  The 
physiology  of  carbohydrate  assimilation  is  not  as  yet 
explained,  and  the  disturbances  which  it  undergoes  are 
equally  obscure. 

The  normal  blood,  it  is  well  known,  contains  a  small 
quantity  of  sugar,  which  occurs  as  glucose  or  grape 
sugar,  and  is  almost  constant  in  amount  (o,  i  per  cent, 
to  0,2  per  cent.),  A  very  minute  quantity  excreted  by 
the  kidneys  can  be  demonstrated  in  the  urine,  but  is 
not  detected  by  the  tests  for  sugar  ordinarily  employed. 
Excretion  of  an  increased  quantity  of  glucose  is  the 
236 


PATHOLOGY    OF    DIABETES   MELLITUS.  237 

most  conspicuous  feature  of  diabetes  mellitus,  but  such 
glycosuria  is  dependent  upon  underlying  metabolic  dis- 
turbances which  manifest  themselves  by  a  variety  of 
other  symptoms.  Increased  excretion  of  sugar  by  the 
urine  can,  however,  occur  without  diabetes,  and  a  va- 
riety of  causes  produce  glycosuria  in  the  absence  of  the 
grave  alterations  of  nutrition  which  characterize  this 
disease. 

Carbohydrates  which  are  ingested  with  the  food,  and 
in  very  great  part  absorbed  as  glucose,  are  carried  to 
the  liver  by  the  portal  circulation,  and  von  Mering  has 
shown  by  direct  observation  that  the  quantity  of  sugar 
in  the  portal  blood  is  increased  after  a  meal.  The  liver 
has  the  power  to  store  up  sugar  carried  to  it  by  the 
blood  ;  Claude  Bernard,  and  later  Schopffer,  found  that 
sugar  injected  into  the  mesenteric  vein  disappears, 
while  an  equal  quantity  injected  into  a  systemic  vein  is 
not  removed  from  the  blood  and  causes  glycosuria. 

Claude  Bernard  made  the  important  discovery  that 
sugar  carried  to  the  liver  is  stored  in  the  form  of  glyco- 
o-en,  which,  when  needed,  is  returned  as  orlucose  to  the 
blood.  After  ingestion  of  carbohydrates  the  amount 
of  glycogen  in  the  liver  increases,  but  disappears  almost 
completely  after  prolonged  abstinence  from  food.  The 
liver,  however,  is  not  the  only  organ  that  stores  glyco- 
gen ;  it  is  present  in  considerable  quantity  in  the  mus- 
cles, being  increased  by  the  ingestion  of  carbohydrates 
in  large  amount  and  diminished  by  hunger  or  by  pro- 


238  DISEASE    OF   THE    PANCREAS. 

lonored  muscular  exertion.  The  muscle  cells  consume 
carbohydrates  during  activity. 

The  ability  of  the  liver  to  transform  glucose  into 
glycogen  is  limited,  and  if  in  a  healthy  man  or  animal  a 
very  large  amount  of  sugar  is  rapidly  absorbed  from 
the  gastro-intestinal  tract,  the  quantity  of  sugar  in  the 
blood  is  increased,  and  is  consequently  excreted  by  the 
urine.  The  liver,  therefore,  acting  as  a  storehouse 
prevents  the  quantity  of  sugar  in  the  blood  from  rising 
above  a  relatively  fixed  amount  (o. i  to  0.2  per  cent.)  ; 
but  if  within  a  given  time  the  capacity  of  the  liver  is 
exceeded,  sugar  accumulates  in  the  blood  and  is  thrown 
off  by  the  kidneys  ;  alimentary  glycosuria  preceded  by 
alimentary  hyperglycsemia  follows,  both  being  the  re- 
sult of  the  limited  capacity  of  the  liver  and  certain  other 
organs  to  store  sugar  absorbed  from  the  food.  This 
limit  varies  in  different  individuals  and  is  diminished 
under  certain  pathological  conditions. 

A  normal  individual  is  able  to  assimilate  from  one 
hundred  and  fifty  to  two  hundred  and  fifty  grammes  of 
glucose  taken  after  fasting,  and  no  sugar  appears  in  the 
urine.  Under  certain  conditions,  notably  in  many  cases 
of  exophthalmic  goitre  and  with  certain  neuroses,  glyco- 
suria follows  the  ingestion  of  much  smaller  quantities. 
Diseased  conditions  of  the  liver  might  be  expected  to 
favor  the  occurrence  of  this  form  of  glycosuria,  and  in 
some  cases  of  cirrhosis  alimentary  glycosuria  is  readily 
produced,  but  the   result  of  such    investigations   have 


PATHOLOGY   OF    DIABETES   MELLITUS.  239 

been  by  no  means  constant.  Minkowski  has  shown 
that  alimentary  glycosuria  may  occur  in  dogs  after  par- 
tial extirpation  of  the  pancreas,  and  Wille  has  demon- 
strated its  association  with  certain  lesions  of  the  human 
ofland. 

Temporary  glycosuria  follows  a  variety  of  injuries  to 
the  nervous  system  ;  the  so-called  diabetic  puncture  of 
Claude  Bernard  is  the  best  known  illustration.  De- 
struction of  the  gray  matter  in  the  floor  of  the  fourth 
ventricle,  a  few  millimetres  above  the  point  of  the  cala- 
mus scriptorius,  in  rabbits,  dogs,  birds,  and  frogs,  is 
followed  by  glycosuria.  In  rabbits,  within  one  to  three 
hours  after  this  operation,  sugar  appears  in  the  urine, 
and  may  constitute  as  much  as  six  per  cent.  ;  excretion 
of  sugar  continues  only  five  or  six  hours.  The  condition 
is  associated  with  an  increase  of  the  sugar  in  the  blood, 
and  a  variety  of  experiments  indicate  that  the  puncture 
causes  a  discharge  of  glycogen  from  the  liver  and 
probably  from  the  muscles  and  other  organs  into  the 
blood,  but  the  evidence  upon  this  point  is  in  part  con- 
flicting. In  animals  deprived  of  glycogen  by  prolonged 
hunger  the  puncture  is  ineffectual,  while  after  section 
of  all  nerves  to  the  liver  glycosuria  is  of  very  slight 
intensity. 

A  variety  of  other  operations  upon  the  nervous  sys- 
tem have  been  followed  by  temporary  glycosuria  pre- 
sumably analogous  with  that  of  Claude  Bernard's 
puncture  ;  glycosuria,  for  example,  has  been  observed 


240  DISEASE    OF   THE    PANCREAS. 

after  extirpation  of  the  superior  cervical  ganglion  after 
section  and  stimulation  of  the  spinal  cord  at  the  level 
of  the  brachial  plexus,  after  stimulation  of  the  central 
stump  of  the  vagus  when  cut,  and  after  section  of  the 
sciatic  nerve  and  stimulation  of  its  central  end. 

One  form  of  glycosuria  which  has  been  the  subject  of 
varied  experimentation  is  unaccompanied  by  an  increase 
of  sugar  in  the  blood.  Following  the  administration  by 
feeding  or  injection  of  the  glucocide  phloridzin  glyco- 
suria occurs  in  man  and  in  lower  animals  and  persists 
often  twenty-four  hours  or  longer,  the  amount  of  sugar 
excreted  greatly  exceeding  that  contained  in  the  gluco- 
cide. The  quantity  of  sugar  in  the  blood  does  not  in- 
crease, even  though  the  kidneys  be  extirpated  or  the 
ureters  ligated  in  order  to  prevent  excretion  of  sugar. 
Pience  it  is  believed  that  the  poison  produces  some 
change,  as  the  result  of  which  the  kidneys  are  no 
longer  able  to  hold  back  the  sugar  normally  present  in 
the  blood.  Minkowski  has  suggested  that  the  glucocide 
phloridzin  is  split  by  the  kidney  into  a  substance,  phlore- 
tin,  and  a  sugar  closely  resembling  glucose  ;  the  latter 
is  excreted,  but  the  phloretin  is  retained  and  unites  with 
more  glucose,  which  is  in  turn  separated  by  the  kidneys, 

Asphyxiation  and  poisoning  with  carbon  monoxide, 
morphine,  curare,  and  a  variety  of  substances  cause  gly- 
cosuria, the  pathogenesis  of  which  is  not  understood.  In 
all  such  instances  the  condition  is  temporary,  and  thus 
distinguishable  from  the  permanent  glycosuria  which  in 


PATHOLOGY   OF    DIABETES    MELLITUS.  241 

man  is  associated  with  the  constitutional  disease  diabetes 
mellitus. 

Permanent  glycosuria  accompanied  by  symptoms  com- 
parable to  those  occurring  in  diabetes  can  be  produced 
by  but  one  experimental  means.  The  epoch-making 
investigations  of  von  Mering  and  Minkowski  on  the 
pancreas  stand  in  importance  next  to  those  of  Claude 
Bernard.  They  have  demonstrated  that  the  organ  is 
essential  to  normal  carbohydrate  metabolism,  and  its 
extirpation  is  followed  by  a  condition  which  reproduces 
in  animals  diabetes  mellitus. 

Extirpation  of  the  Pancreas. — Observations  of  von 
Mering  and  Minkowski,  later  amplified  by  Minkowski, 
have  shown  that  complete  removal  of  the  pancreas  in 
dogs  is  followed  within  twenty-four  hours  by  the  appear- 
ance of  sugar  in  the  urine.  The  quantity  of  sugar  grad- 
ually increases,  and  usually  reaches  a  maximum  on  the 
third  day,  when  it  may  form  from  eight  to  ten  per  cent., 
even  though  no  carbohydrates  have  been  taken  into  the 
gastro-intestinal  tract.  Glycosuria  continues  and  is 
associated  with  a  corresponding  hyperglycaemia.  Gly- 
cogen disappears  almost  completely  from  the  liver  and 
other  organs.  Symptoms  analogous  to  those  of  human 
diabetes  occur,  and  there  is  greatly  increased  appetite 
and  excessive  thirst,  accompanied  by  increase  in  the 
amount  of  urine  ;  gradual  emaciation  and  progressive 
weakness  precede  death,  which  occurs  several  weeks 
after  the   operation.      Acetone  and  diacetic   and  oxy- 

16 


24: 


DISEASE    OF   THE    PANCREAS. 


butyric  acid  have  been  found  in  the  urine.  Minkowski 
observed  that  grape  sugar  taken  with  the  food  is  com- 
pletely excreted  by  the  urine.  Since  glycosuria  con- 
tinues even  when  the  diet  is  entirely  free  from  carbo- 
hydrates, sugar  must  be  formed  within  the  body  ;  the 
amount  bears  a  constant  ratio  (2,8  :  i)  to  the  quantity 
of  nitrogen  eliminated.  This  constant  ratio  is  best  ex- 
plained by  supposing  that  the  total  quantity  of  sugar 
formed  in  the  body  from  albumin  is,  after  removal  of 
the  pancreas,  excreted  by  the  kidneys.  Immediately 
before  the  fatal  termination  of  the  disease,  when  emacia- 
tion and  weakness  are  extreme,  and  particularly  with 
the  onset  of  complications, — for  example,  suppurative 
peritonitis  as  a  consequence  of  the  operation, — sugar 
may  disappear  from  the  urine.  A  similar  phenomenon 
is  observed  in  human  diabetes,  and  is  doubtless  due  to 
some  interference  with  the  absorption  of  sugar  or  with 
its  production  within  the  body  from  proteids. 

Partial  removal  of  the  pancreas — if  a  considerable 
portion,  a  fourth  or  a  fifth,  remains — is  not  followed  by 
diabetes,  but  a  smaller  part — for  example,  an  eighth  or 
a  twelfth — does  not  suffice  to  prevent  its  onset.  In  such 
case  the  severity  of  the  disease  is  very  variable,  and 
may  be  indicated  by  an  intolerance  of  the  organism  for 
sugar,  a  very  small  quantity  taken  as  food  causing  ali- 
mentary glycosuria.  Alimentary  glycosuria  may  there- 
fore indicate  partial  insufficiency  of  the  pancreas. 

Experiments,  always  with  negative  results,  have  been 


PATHOLOGY    OF    DIABETES    MELLITUS.  243 

undertaken  to  show  that  injury  to  the  organs  surround- 
ing the  pancreas,  particularly  to  the  nerves  and  ganglia, 
is  responsible  for  the  resulting  disturbances  of  meta- 
bolism. Slight  injury  to  the  pancreas  not  infrequently 
causes  transient  glycosuria,  but  never  diabetes.  That 
the  disease  is  not  caused  by  inhibition  of  the  pancre- 
atic secretion  or  by  its  removal  from  the  intestine  is 
shown  by  the  absence  of  glycosuria  after  ligation  of  the 
pancreatic  ducts  or  after  the  formation  of  a  pancreatic 
fistula  ;  though  the  pancreatic  juice  fails  to  reach  the 
intestine  diabetes  does  not  result. 

The  observations  of  von  Mering  and  Minkowski  on 
dogs  have  been  confirmed  by  a  very  large  number  of 
experiments,  and  extended  observations  indicate  that 
they  are  applicable  to  all  classes  of  vertebrates.  In 
rare  instances  discordant  results  have  been  obtained, 
but  have  doubtless  been  due  to  the  mechanical  difficulty 
of  completely  removing  the  gland.  Diabetes  has  been 
produced  in  cats  and  in  pigs  by  Minkowski.  Both 
Weintraud  and  Kausch  have  removed  the  gland  from 
various  birds, — namely,  ducks,  geese,  falcons,  buzzards, 
and  ravens, — and  have  observed  glycosuria  persisting 
until  death.  Of  considerable  interest,  however,  is  the 
fact  demonstrated  by  Kausch  that  in  geese  and  ducks 
the  lesion  is  not  constantly  followed  by  glycosuria, 
although  the  quantity  of  sugar  in  the  blood  is  increased 
as  in  other  species.  It  appears  that  sugar  is  not  readily 
excreted  by  the  kidneys  of  these  animals.     Glycosuria 


244 


DISEASE    OF   THE    PANCREAS. 


with  fatal  termination  has  been  shown  to  follow  the 
operation  in  frogs  and  in  turtles  (Aldehoff ),  and  in  eels 
(Capparelli), 

The  pancreas  of  vertebrates  is  therefore  essential 
to  carbohydrate  metabolism,  and  removal  or  destruction 
is  followed  by  the  accumulation  of  sugar  in  the  blood 
and  its  excretion  by  the  kidneys.  How  does  the  pan- 
creas influence  metabolism  ?  Abundant  observation  has 
demonstrated  that  injury  to  the  nerves  of  the  pancreas 
is  not  responsible  ;  failure  of  the  pancreatic  juice  to 
reach  the  intestine  is  not  its  cause,  since  ligation  of 
the  pancreatic  ducts  is  not  followed  by  diabetes.  Fur- 
thermore, after  partial  removal  of  the  gland  its  splenic 
extremity,  alone  remaining,  may  be  transplanted  into 
the  subcutaneous  tissue  without  complete  destruction 
of  its  vascular  connections.  The  nerves  of  the  resected 
part  are  severed  and  the  pancreatic  juice  is  wholly  lost, 
yet  glycosuria  does  not  follow  ;  if  now  the  transplanted 
part  be  removed,  diabetes  ensues. 

The  pancreas  may  influence  carbohydrate  metabo- 
lism in  two  ways  :  the  organ  may  furnish  something 
essential  to  normal  nutrition,  an  internal  secretion  (to 
be  distinguished  from  the  pancreatic  juice,  the  external 
secretion),  or  the  gland  may  destroy  some  product 
.which  accumulates  in  the  body  and  hinders  normal  as- 
similation of  sugar.  The  experimental  evidence  avail- 
able is  insufficient  to  decide  the  relative  importance  of 
these  possibilities.      Lepine  has  believed  that  he  was 


PATHOLOGY    OF    DIABETES   MELLITUS  245 

able  to  demonstrate  in  the  blood  a  glycolytic  ferment 
capable  of  transforming  sugar.  He  claims  that  it  is 
present  in  normal  blood,  but  absent  in  that  of  lower 
animals  or  human  beings  suffering  with  diabetes.  This 
ferment,  he  thinks,  is  formed  in  the  pancreas,  from 
which  it  is  carried  by  the  lymph  or  blood  to  the  tissues 
and  there  furthers  carbohydrate  assimilation.  The  basis 
of  Lepine's  theory  is  the  observation  of  Claude  Ber- 
nard that  sugar  disappears  from  drawn  blood  ;  Lepine 
believes  that  this  glycolysis  is  diminished  in  diabetic 
patients  and  in  dogs  from  which  the  pancreas  is  re- 
moved. Almost  all  observers  who  have  repeated  his 
experiments  have  obtained  negative  results.  The  suc- 
cess of  thyroid  therapy  in  the  treatment  of  diseases 
presumably  due  to  the  absence  of  an  internal  secretion 
produced  by  the  thyroid  gland  has  pointed  the  way  to 
numerous  analogous  experiments  upon  animals  suffer- 
ing with  diabetes,  but  glycosuria  has  not  been  prevented 
nor  diminished  by  the  administration  of  products  ob- 
tained from  the  pancreas. 

Since  sugar  is  excreted  in  the  urine  after  removal  of 
the  pancreas,  even  though  carbohydrates  are  not  taken 
with  the  food,  it  is  evident  that  glucose  can  be  formed 
within  the  body.  Since  the  amount  of  sugar  in  the 
urine  bears  a  constant  ratio  to  the  nitrogen  excreted,  - 
there  can  be  little  doubt  that  sugar  is  formed  from  pro- 
teids,  and  that  the  entire  amount  of  sup-ar  thus  formed 
is  unassimilated   and  excreted.     An  additional  fact  of 


246  DISEASE    OF   THE   PANCREAS. 

considerable  interest  is  the  disappearance  of  glycogen 
from  the  liver  and  muscles  after  extirpation  of  the  pan- 
creas. Hence  it  appears  that  removal  of  the  gland 
renders  the  tissues  unable  to  take  up  and  assimilate 
sugar.  The  inability  of  the  liver  to  transform  sugar 
into  glycogen  applies  to  glucose,  but  not  to  the  iso- 
metric levorotatory  sugar  levulose, — for  after  ingestion 
of  the  latter  glycogen  is  found  in  the  liver.  Schmiede- 
berg  has  suggested  that  in  diabetes  glucose  in  the 
blood  is  combined  with  some  substance  which  prevents 
its  assimilation  by  the  tissues.  The  tissues  are  never- 
theless able  to  take  up  the  molecule  of  levulose.  A 
somewhat  analogous  explanation  of  phloridzin  dia- 
betes advanced  by  Minkowski  has  already  been  men- 
tioned. 

Pancreatic  Diabetes. — The  experimental  studies  just 
described  have  demonstrated  the  dependence  of  car- 
bohydrate assimilation  upon  the  pancreas  and  have 
shown  that  its  removal  is  followed  by  a  condition  iden- 
tical with  diabetes  mellitus.  They  suggest  a  probable 
relationship  between  this  disease  and  lesions  of  the 
o-land  in  man. 

A  century  before  the  discoveries  of  von  Mering  and 
Minkowski  the  association  of  diabetes  with  grave 
lesions  of  the  orphan  had  been  observed,  and  since 
both  conditions  are  relatively  uncommon,  a  casual  rela- 
tionship had  suggested  itself  Careful  study  has  failed 
to  demonstrate  the  constant  presence  of  pancreatic  dis- 


PATHOLOGY    OF    DIABETES    MELLITUS  247 

ease,  even  when  special  attention  has  been  directed  to 
the  organ,  and  by  many  writers  it  has  been  claimed  that 
in  only  an  insignificant  number  of  cases  is  diabetes  refer- 
able to  a  lesion  of  the  pancreas. 

As  early  as  1788  Thomas  Cawley  described  a  case 
of  diabetes  associated  with  pancreatic  calculi  and  con- 
sequent atrophy  of  the  gland.  Bright  in  1833  recorded 
a  case  in  which  the  pancreas  was  the  seat  of  carcinoma 
compressing  the  duct  and  causing  atrophy.  Bouchardat 
in  1875  directed  attention  to  the  association  of  diabetes 
with  lesions  of  the  pancreas,  and  Lancereaux  several 
years  later  claimed  that  diabetes  accompanied  by  wast- 
ing is  the  result  of  disease  of  the  gland,  while  diabetes 
without  wasting  is  dependent  upon  other  factors  ;  but 
numerous  subsequent  observations  have  failed  to  con- 
firm this  clinical  distinction  between  pancreatic  and  non- 
pancreatic diabetes.  The  experimental  observations  of 
von  Mering  and  Minkowski  having  established  in  dogs 
a  relationship  between  the  pancreas  and  diabetes,  a 
renewed  interest  was  given  the  study  of  the  gland  in 
this  disease.  Such  investigation  has  shown  that  though 
lesions  occur  in  a  considerable  proportion  of  cases, 
on  the  one  hand  all  cases  of  diabetes  are  not  accom- 
panied by  demonstrable  lesions  of  the  pancreas,  and 
on  the  other  hand  all  lesions  of  the  pancreas  are  not 
associated  with  diabetes. 

Hansemann    in    1894    collected  from    the   literature 
cases  in  which  diabetes  was  accompanied  by  pancreatic 


248 


DISEASE    OF    THE    PANCREAS. 


lesions.     In  seventy-two  cases  the  following  alterations 
of  the  gland  occurred  : 

Pancreatic  calculi  .  .  .  .  .14  cases. 

Carcinoma  with  obstruction  of  the  duct  .  .  5      " 

Simple  atrophy  and  interstitial  inflammation  .        38     " 

Other  lesions        .  .  .  .  .  .        15      " 

Such  a  summary  of  isolated  cases  reported  by  differ- 
ent observers,  in  many  instances  without  microscopic  ex- 
amination of  the  gland,  gives  no  accurate  conception  of 
the  relative  frequency  of  various  lesions.  Uncommon 
conditions — for  example,  calculi  and  carcinoma — are 
more  likely  to  be  reported.  Among  the  unclassified 
lesions  noted  by  Hansemann  is  necrosis  of  the  gland. 
There  are  also  included  a  number  of  insignificant 
lesions, — for  example,  hyperaemia  and  fatty  degenera- 
tion of  the  parenchyma,  conditions  which  are  in  a  great 
majority  of  instances  unassociated  with  diabetes  and 
are  doubtless  not  responsible  for  its  occurrence. 

Dieckhoff  studied  seven  cases  of  diabetes,  in  all  of 
which  the  pancreas  was  diseased,  and  from  the  literature 
collected  others  in  which  the  condition  was,  he  believed, 
referable  to  the  gland.  In  forty-nine  cases  the  lesion 
was  as  follows  : 


Acute  pancreatitis  . 

5  cases 

Chronic  pancreatitis 

.      15      " 

Carcinoma     . 

.        4     " 

Atrophy,  lipomatosis 

.      21      " 

Cysts    .... 

.        4      " 

PATHOLOGY    OF    DIABETES    MELLITUS  249 

Statistics  of  the  older  writers  not  based  upon  careful 
macroscopic  and  microscopic  examination  of  the  gland 
are  of  little  value,  and  those  of  Windle  (pancreatic 
lesions  present  in  seventy-four  of  one  hundred  and 
thirty-nine  cases  of  diabetes),  of  Seegen  (seventeen  of 
ninty-two),  and  of  others,  admit  no  trustworthy  conclu- 
sions. 

Much  more  accurate  statistics  are  obtainable,  as 
Hansemann  recog-nized  from  a  series  of  consecutive 
cases.  In  the  Pathological  Institute  in  Berlin  he  studied 
fifty-four  cases,  of  which  in  forty  occurred  lesions  of  the 
pancreas  ;  in  six  no  note  was  made  upon  the  gland  ; 
while  in  eight,  though  it  was  examined,  no  lesion  was 
found. 

The  lesions  observed  were  as  follows  : 

Atrophy  (granular)      .  .  .  .  .  .  36 

Fibrous  induration  (with  hypertrophy)  ...  3 

Complicated  case  ......  i 

Williamson  studied  twenty-three  cases  of  diabetes,  of 
which  in  twenty-two  the  pancreas  was  examined  micro- 
scopically. In  twelve  cases  the  gland  was  normal  (eight 
cases)  or  atrophied  (four  cases)  to  a  degree  not  out  of 
proportion  to  the  wasting  of  other  organs.  In  four  cases 
chronic  interstitial  pancreatitis  was  present,  in  one  lipo- 
matosis, in  two  atrophy  with  fatty  degeneration,  in  three 
atrophy  without  other  lesion,  and  in  one  carcinoma. 

I  have  examined  the  pancreas  from  nineteen  cases  of 


250 


DISEASE   OF   THE    PANCREAS. 


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PATHOLOGY   OF    DIABETES    MELLITUS  251 

diabetes,  and  in  all  the  condition  of  the  various  histo- 
logical elements  of  the  gfland  has  been  noted.  These 
data  are  collected  in  the  accompanying  table  (see  p. 
250).  Many  of  these  cases  have  been  previously  cited 
in  describing  some  of  the  peculiar  lesions  to  which  the 
organ  is  subject.  The  condition  of  the  pancreas  noted 
in  the  table  is  as  follows  : 

Chronic  interlobular  pancreatitis  with  calculi     .  .  i 

Chronic  interacinar  pancreatitis       ....  3 

Hyaline  degeneration  of  the  islands  of  Langerhans 
(Case  XXXI.  included)   with,  in  some  instances, 

chronic  interacinar  pancreatitis     ....  7 

Atrophic  pancreas  .......  4 

Normal  pancreas    .......  4 

The  following  grave  lesions  of  the  pancreas  have  been 
found  associated  with  diabetes  by  the  various  writers 
cited  :  carcinoma  destroying  the  gland  ;  acute  pancre- 
atitis, usually  with  hemorrhagic  necrosis  of  the  organ  ; 
chronic  interstitial  pancreatitis  following  obstruction  of 
the  ducts  by  calculi,  cysts,  or  carcinomata  ;  chronic  inter- 
stitial pancreatitis  due  to  other  causes  ;  simple  atrophy 
of  the  pancreas.  Certain  features  associated  with  each 
of  these  conditions  demand  consideration,  but  it  is  un- 
necessary to  discuss  the  relationship  to  diabetes  of  less 
important  alterations, — for  example,  hyperaemia,  paren- 
chymatous and  fatty  degeneration,  which  so  commonly 
occur  without  any  disturbance  of  carbohydrate  metab- 
olism. 


252 


DISEASE    OF   THE    PANCREAS. 


Destructive  Lesions  of  the  Pajicreas  with  Diabetes. — 
Though  complete  removal  of  the  pancreas  in  lower 
animals  is  followed  by  diabetes,  numerous  writers  have 
claimed  that  in  man  complete  destruction  of  the  organ, 
which  may  be  the  result  of  necrosis  following  hemor- 
rhagic inflammation  or  of  carcinoma  invading  and  de- 
stroying the  gland,  is  not  invariably  followed  by  diabetes. 
Hansemann  has  considered  at  length  the  evidence  in 
favor  of  this  objection  to  a  pancreatic  origin  of  the  disease. 

Acute  inflammation  of  the  pancreas  associated  with 
suppuration  or  necrosis  may  cause  extensive  destruc- 
tion of  the  gland,  yet  in  only  two  of  about  one  hundred 
cases  cited  by  Fitz  and  by  Seitz  was  diabetes  present. 
Total  destruction  of  the  pancreas  caused  by  acute  in- 
flammation is  quickly  followed  by  death,  with  symptoms 
of  great  severity  ;  in  less  rapidly  fatal  cases  the  whole 
organ  is  not  implicated.  After  extirpation  of  the  pan- 
creas, moreover,  a  variable  time  elapses  before  sugar 
appears  in  the  urine  ;  and  in  most  cases,  shortly  before 
the  fatal  termination  or  with  the  onset  of  severe  com- 
plications, glycosuria  disappears. 

Destruction  of  the  pancreas  may  be  caused  by  dif- 
fuse carcinomatous  new  growth  invading  the  organ  and 
replacing  the  parenchyma.  In  another  category  belong 
those  more  frequent  instances  in  which  a  new  growth 
compressing  the  duct  has  produced  secondary  chronic 
inflammation  of  the  gland.  Hansemann  describes  two 
cases  in  which  a  difl"use  primary  carcinoma  of  the  pan- 


PATHOLOGY    OF    DIABETES    MELLITUS  25 


0 


creas  had  caused  such  complete  destruction  of  the 
organ  that  no  glandular  tissue  was  recognizable  in  the 
sections  which  he  examined  ;  diabetes,  however,  was 
absent.  He  suggests  that  though  the  gland  can  no 
longer  produce  an  external  secretion, — the  pancreatic 
juice — the  tumor  cells  derived  from  the  parenchyma  of 
the  gland  are  still  capable  of  exerting  that  influence 
upon  carbohydrate  metabolism  which  favors  the  assimi- 
lation of  suear  ;  the  internal  function  is  not  lost.  He 
cites  the  observation  not  infrequently  made  that 
primary  carcinoma  of  the  adrenal  is  usually  unaccom- 
panied by  Addison's  disease. 

The  difficulty  of  identifying  within  a  carcinomatous 
mass  small  indurated,  but  yet  well  preserved,  areas  of 
pancreatic  parenchyma  should  be  recognized  ;  and  even 
though  the  secreting  acini  have  been  destroyed,  it  is 
possible  that  islands  of  Langerhans,  which  superficially 
resemble  alveoli  of  carcinomatous  cells,  may  still  per- 
sist. On  the  other  hand,  as  Ssobolow  has  pointed  out, 
should  we  believe  that  the  internal  function  of  the  pan- 
creas is  performed  by  the  islands  of  Langerhans,  carci- 
nomata  arising  from  these  structures  could  alone  sup- 
ply this  deficiency. 

Atrophy  of  the  Pancreas  zvith  Diabetes. — Accompany- 
ing diabetes  diminution  in  the  size  of  the  pancreas  has 
been  more  frequently  noted  than  any  other  abnormality 
of  the  gland.  The  normal  organ  is  subject  to  much 
variation,  and    its   weight  is   differently   estimated   by 


254 


DISEASE    OF    THE    PANCREAS. 


anatomists.  Vierordt  has  given  the  normal  weight  as 
from  eighty-eight  to  one  hundred  and  two  grammes,  and 
Hansemann  thinks  that  it  more  frequently  approaches 
the  larger  than  the  smaller  figure  ;  Kraus  gives  from 
sixty-seven  to  one  hundred  and  five  grammes.  Doubt- 
less a  weight  below  sixty-five  grammes  should  be 
regarded  as  abnormal.  So-called  atrophy  has  been 
frequently  associated  with  severe  alterations  of  the 
parenchyma,  notably  with  chronic  interstitial  inflamma- 
tion, in  some  instances  following  occlusion  of  the  pan- 
creatic duct,  and  such  cases  are  to  be  separated  from 
those  in  which  the  tissue  presents  a  normal  histological 
character. 

Hansemann  discusses  the  relationship  of  atrophy 
to  diabetes.  Is  it  a  consequence  of  the  general  ema- 
ciation associated  with  diabetes,  and  is  it  therefore 
secondary  to  this  disease  ?  The  pancreas  doubtless 
shares  the  atrophy  which  all  organs  undergo  as  the 
result  of  cachexia  from  any  cause  ;  but  since  the  pan- 
creas is  little  affected,  although  the  other  organs  of  an 
emaciated  individual  are  much  diminished  in  weight, 
Hansemann  concludes  that  only  a  slight  diminution  in 
size  can  be  secondary  to  diabetes.  Moreover,  atro- 
phy of  the  pancreas  is  not  limited,  as  Lancereaux  sup- 
posed, to  those  cases  of  diabetes  accompanied  by  ema- 
ciation, for  Hansemann  found  that  of  thirty-six  cases  in 
which  the  pancreas  was  atrophied,  in  six  instances  the 
affected  individual  was  corpulent. 


PATHOLOGY   OF    DIABETES   MELLITUS.  255 

Hansemann,  however,  attempts  to  make  an  anatomi- 
cal distinction  between  the  so-called  atrophy  of  diabetes 
and  the  less  marked  atrophy  of  general  cachexia.  The 
distinction  which  he  draws  removes  the  former  from  the 
domain  of  simple  atrophy  and  characterizes  it  as  a 
variety  of  chronic  interstitial  inflammation.  Neverthe- 
less, in  a  carefully  studied  series  of  cases  Williamson 
has  demonstrated  the  co-existence  of  diabetes  and  ex- 
treme diminution  in  the  size  of  the  pancreas  unasso- 
ciated  with  any  demonstrable  alteration  of  the  paren- 
chyma. In  five  of  twenty-three  cases  the  pancreas  was 
atrophied  to  an  extent  bearing-  no  relationship  to  the 
general  wasting  of  the  other  organs.  In  two  of  these 
cases  the  glandular  cells  showed  fatt}^  degeneration,  but 
in  three  cases  the  parenchyma  appeared  to  be  normal. 
In  one  instance  the  organ  in  a  man  weighed  only  a 
quarter  of  an  ounce  (eight  grammes). 

In  four  of  my  cases  the  pancreas  was  diminished  in 
size  (three  glands  weighing  60,  58,  and  51  grammes 
in  individuals  respectively  forty-six,  fifty-six,  and  thirty 
years  of  age,  the  fourth,  54.5  in  an  old  woman  whose 
age  was  not  known),  but  no  other  alterations  were  ob- 
servable. Since  the  gland  shows  no  structural  change, 
it  is  conceivable  that  the  condition  is  congenital,  and  the 
pancreas  being  unusually  small,  at  some  period  of  life 
fails  to  meet  the  demand  made  upon  it,  so  that  diabetes 
results.  The  data  at  hand,  however,  are  insufficient  to 
establish  this  hypothesis. 


256  DISEASE    OF   THE    PANCREAS. 

Chronic  Interstitial  Pancreatitis  with  Diabetes. — The 
association  of  chronic  interstitial  inflammation  with  dia- 
betes has  been  very  frequently  observed.  In  some 
instances  chronic  inflammation  has  followed  obstruction 
of  the  pancreatic  duct  by  calculi,  carcinoma  of  the  head 
of  the  gland  or  cysts  causing  compression  of  the  ducts, 
and  such  cases  are  cited  in  the  statistics  of  Windle, 
Hansemann,  and  Dieckhoff  Though  a  considerable 
number  of  cases  has  been  reported,  the  condition  is  rel- 
atively uncommon  ;  and  where  consecutive  cases  of  dia- 
betes have  been  studied  by  one  observer,  duct-obstruc- 
tion is  found  to  be  relatively  infrequent.  In  none  of 
forty  cases  did  Hansemann  find  sclerosis  consequent 
upon  the  presence  of  calculi,  but  in  two  examples  of 
advanced  sclerosis  with  calculi  diabetes  was  absent. 
Williamson  found  among  his  twenty-three  cases  of  dia- 
betes one  with  sclerosis  following  stone-formation. 

In  only  one  of  the  cases  which  I  have  described  did 
diabetes  accompany  pancreatic  calculi ;  here  the  con- 
sequent induration  of  the  gland  and  destruction  of  its 
parenchyma  were  far  advanced.  Of  considerable  im- 
portance is  the  fact  that  the  associated  diabetes  was  of 
mild  character,  glycosuria  disappearing  when  carbohy- 
drates were  withdrawn  from  the  diet.  On  the  other 
hand,  in  two  of  my  cases  with  advanced  sclerosis  fol- 
lowing obstruction  of  the  pancreatic  duct — in  one  case 
caused  by  calculi  (Case  XII.),  in  another  by  carcinoma 
(Case  IX.) — diabetes  was  absent.     Ligation  of  the  pan- 


PATHOLOGY   OF    DIABETES   MELLITUS.  257 

creatic  ducts  in  animals  is  rarely,  if  ever,  followed  by 
diabetes.  The  severe  inflammatory  changes  which  in 
human  beings  follow  duct-obstruction,  associated  in 
most  instances  with  conditions  favoring  ascending  infec- 
tion with  bacteria,  are  followed  by  diabetes  only  when 
they  have  reached  such  an  advanced  stage  that  the 
parenchyma  is  almost  wholly  replaced  and  compressed 
by  dense  fibrous  tissue.  The  relationship  of  the  lesion 
to  the  histological  elements  of  the  gland  will  be  dis- 
cussed later. 

Chronic  pancreatitis  due  to  causes  other  than  duct- 
obstruction  is  not  infrequently  associated  with  diabetes, 
but  chronic  pancreatitis  is  not  always,  or  indeed  in  the 
majority  of  instances,  accompanied  by  diabetes.  Since 
experimental  investigations  have  shown  that  in  order  to 
produce  glycosuria  it  is  necessary  to  remove  a  large 
part  of  the  pancreas,  we  need  not  expect  the  condition 
with  chronic  inflammation  unless  a  great  part  of  the 
parenchyma  has  been  destroyed  or  functionally  im- 
paired. 

Various  observers  have  attempted  to  define  a  type  of 
pancreatitis  peculiar  to  diabetes.  G.  Hoppe-Seyler  and 
Fleiner  have  described  cases  of  the  disease  in  which 
chronic  interstitial  inflammation  of  the  organ  accom- 
panied general  arterial  sclerosis.  Lemoine  and  Lannois, 
as  already  noted,  have  studied  pancreatitis  in  four  cases 
of  diabetes,  and  have  thought  that  the  new  growth  of 
interstitial  tissue  has  its  seat  of  origin  in  the  perivascular 

17 


258  DISEASE    OF   THE    PANCREAS. 

tissue,  whence  fibrous  processes  extend  between  the 
parenchymatous  structures.  An  important  feature  of 
the  inflammatory  change  described  by  them  is  the 
penetration  of  fibrous  strands  into  the  acini,  separating 
the  cells  and  producing  what  they  designate  unicellular 
sclerosis. 

Hansemann  has  claimed  that  one  variety  of  pancrea- 
titis is  always  accompanied  by  diabetes.  He  desig- 
nates the  condition  atrophy,  but  the  character  of  the 
lesion  and,  what  he  particularly  emphasizes,  the  features 
which  distinguish  it  from  atrophy  consequent  upon  ema- 
ciation identify  it  as  chronic  inflammation.  The  organ 
is  diminished  in  size  and  is  flattened  from  before  back. 
Its  increased  interstitial  tissue  is  in  continuity  with  that 
of  the  adjacent  structures,  and  consequently  removal 
of  the  organ  is  more  difficult  than  usual.  The  micro- 
scope demonstrates  an  atrophy  of  the  parenchymatous 
elements  which  are  in  part  replaced  by  new  fibrous  tis- 
sue. With  cachectic  atrophy,  on  the  contrary,  gland- 
ular cells  and  interstitial  tissue  have  undergone  equal 
atrophy.  Hansemann  thinks  that  this  pancreatic  lesion 
characteristic  of  diabetes  is  similar  to  certain  forms  of 
granular  atrophy  of  the  kidneys.  Since  the  new  growth 
of  interstitial  tissue  is  always  accompanied  by  diminu- 
tion in  the  size  of  the  organ,  he  distinguishes  granular 
atrophy  from  fibrous  induration  with  hypertrophy,  which 
in  three  instances  he  found  associated  with  diabetes. 
This  fibrous  induration  characterized  by  coarse  bands 


PATHOLOGY   OF   DIABETES    MELLITUS.  259 

of  newly-formed  stroma  is  usually  unaccompanied  by 
diabetes. 

In  a  preceding  chapter  I  have  shown  that  two  forms 
of  chronic  inflammation  of  the  sfland  are  distinguish- 
able  :  (1)  interlobular  pancreatitis,  characterized  by  pro- 
liferation of  fibrous  tissue  between  the  lobules  which  are 
invaded  from  the  periphery,  and  (2)  interacinar  pancrea- 
titis, where  the  newly-formed  fibrous  tissue  is  more 
diffusely  distributed  within  the  lobules  and  between  indi- 
vidual acini.  With  the  first  type  the  islands  of  Langer- 
hans  are  implicated  only  when  the  sclerotic  process  has 
reached  a  very  advanced  grade.  To  this  variety  be- 
longs the  chronic  inflammation  which  follows  occlusion 
of  the  pancreatic  duct.  Though  the  secreting  tissue  of 
the  gland  is  in  very  great  part  destroyed  and  replaced 
by  dense  fibrous  tissue,  the  interacinar  islands  are  not 
affected  and  persist  for  a  long  time  as  isolated  cellular 
structures  almost  completely  unchanged,  though  sur- 
rounded by  scar-like  tissue  ;  they  suffer  only  when  the 
process  is  far  advanced.  With  the  interacinar  type  of 
inflammation,  on  the  other  hand,  the  islands  are  affected 
as  are  the  other  elements  of  the  grland,  and  coarse 
strands  of  fibrous  stroma  following  the  capillary  ves-  . 
sels  separate  columns  of  atrophied  cells. 

Should  there  be  a  type  of  pancreatitis  peculiar  to  dia- 
betes,— that  is,  a  form  of  inflammation  impairing  the 
internal  function  of  the  gland, — glycosuria  would  not 
ensue  until  the  lesion  had  reached  a  certain  grade  of 


2  6o  DISEASE    OF    THE   PANCREAS. 

intensity,  and  in  its  earliest  stage  the  lesion  would  not 
be  accompanied  by  diabetes.  On  the  other  hand,  when 
chronic  interstitial  pancreatitis,  whatever  the  type  may 
be,  has  destroyed  a  very  large  part  of  the  parenchyma, 
diabetes  may  be  expected  ;  the  specific  type,  should 
such  exist,  would  be  associated  with  the  disease  at  an 
earlier  stage. 

Of  twenty-one  instances  of  chronic  pancreatitis  of  the 
interlobular  type  in  only  one  was  diabetes  present. 
Here,  as  mentioned  above,  the  inflammation  which  fol- 
lowed obstruction  of  the  pancreatic  duct  had  reached  a 
very  advanced  grade,  and  the  islands  of  Langerhans, 
isolated  in  the  dense  stroma,  had  undergone  altera- 
tions ;  the  accompanying  glycosuria  had  been  of  slight 
severity  and  had  disappeared  when  the  patient  was 
upon  a  diet  poor  in  carbohydrates.  In  seven  of  nine 
instances  of  interacinar  pancreatitis,  diabetes  mellitus 
was  present.  In  one  case  without  diabetes  the  lesion 
was  but  little  advanced,  and  the  organ  was  of  large  size, 
weighing  one  hundred  and  seventy  grammes  ;  while  in 
the  other  case  the  lesion  was  of  such  slight  intensity  as 
to  be  unrecognizable  in  many  parts  of  the  tissue. 


CHAPTER    XI. 

THE     RELATION     OF     DIABETES     MELLITUS     TO     LESIONS     OF 
THE    PANCREAS. 

Relation  of  Diabetes  to  Lesions  of  tJie  Islands  of  Lan- 
gerhans. — For  the  purpose  of  the  present  study  it  is 
pertinent  to  inquire  what  histological  changes  in  the  pan- 
creas are  associated  with  the  occurrence  of  diabetes. 
When  a  lesion  of  the  pancreas  is  the  cause  of  the  dis- 
ease, is  the  condition  dependent  upon  changes  in  the 
acini  or  in  the  islands  of  Langerhans  or  in  both  ?  Total 
destruction  of  the  acini  is  often  accompanied  by  destruc- 
tion or  alteration  of  the  interacinar  structures,  and  rarely 
are  the  islands  of  Langerhans  the  seat  of  marked  lesion 
while  the  acini  remain  unchanged. 

The  islands  of  Langerhans  are  composed  of  columns 
of  cells  having  no  communication  with  the  ducts  of  the 
gland,  but  in  intimate  relation  with  a  rich  capillary  net- 
work, and  an  analogous  condition  is  found  in  the  thyroid 
gland  and  in  the  adrenal.  The  pancreas,  as  do  these 
organs,  exerts  through  the  medium  of  the  blood  an 
important  influence  on  metabolism.  Whether  the 
gland  furnishes  some  substance  which  aids  carbo- 
hydrate assimilation  or  destroys  some  noxious  product 

hindering  it  is  immaterial  to  the  present  study.     Where 

261 


262  DISEASE   OF   THE    PANCREAS. 

diabetes  is  the  result  of  pancreatic  disease,  do  the 
islands  of  Langerhans  exhibit  lesions  ? 

With  the  interacinar  type  of  chronic  pancreatitis, 
which,  except  in  its  earliest  stage,  is  accompanied  by 
diabetes,  the  islands  of  Langerhans  are  invaded  by  the 
inflammatory  process.  With  the  interlobular  type, 
which  may  follow  obstruction  of  the  pancreatic  ducts  or 
ascending  infection  of  the  gland,  diabetes  ensues  only 
in  those  relatively  uncommon  instances  in  which  the 
lesion  has  reached  a  very  advanced  grade ;  the  sclerotic 
process,  which  in  many  cases  at  least  has  its  origin  in 
the  ducts  of  the  gland,  spares  the  islands  of  Langerhans 
and  causes  their  destruction  only  when  the  gland  is 
almost  wholly  transformed  into  dense  sclerotic  stroma. 
These  facts,  however,  do  not  demonstrate  with  cer- 
tainty the  dependence  of  diabetes  upon  alterations  of 
the  islands  of  Langerhans,  for  on  the  one  hand  with 
interacinar  pancreatitis  the  secreting  parenchyma  is 
equally  affected,  while  on  the  other  hand,  in  instances  of 
interlobular  inflammation,  the  secreting  alveoli  are  pre- 
served, even  when  the  lesion  is  far  advanced. 

In  a  preceding  chapter  I  have  shown  the  suscepti- 
bility of  the  pancreas  to  hyaline  degeneration.  The  first 
example  of  the  lesion  which  came  to  my  observation 
was  accompanied  by  a  severe  type  of  diabetes,  and 
though  the  islands  were  so  altered  as  to  be  completely 
unrecognizable,  the  secreting  parenchyma  was  in  great 
part  destroyed.     The  succeeding  instances  of  this  re- 


THE   PATHOLOGY    OF    DIABETES    MELLITUS.     263 

markable  lesion  clearly  demonstrated  the  relationship 
of  diabetes  to  a  destructive  lesion  of  the  islands,  for 
though  these  structures  had  undergone  very  grave 
alterations  and  were  often  converted  into  almost  homo- 
geneous hyaline  masses,  the  secreting  parenchyma, 
notably  in  Cases  XXVI.  and  XXVII. ,  showed  only  a 
very  insignificant  increase  of  the  stroma,  which  in 
many  parts  of  the  gland  was  wholly  unaltered. 

Subsequent  observations  have  demonstrated  the 
surprising  frequency  with  which  this  selective  lesion 
accompanies  diabetes,  and  in  six  of  the  nineteen  cases 
of  diabetes  which  I  have  studied  it  has  been  found. 
In  three  of  these  cases,  XXVI.,  XXVII.,  and  XXVIII., 
described  in  detail,  the  lesion  of  the  islands  had  doubt- 
less been  of  such  a  character  as  to  render  them  almost 
completely  functionless,  though  the  remaining  paren- 
chyma was  relatively  well  preserved.  The  other  cases, 
including  Case  XXXI.,  in  which  the  lesion  resembled 
coagulative  necrosis  of  the  liver,  could  not  be  studied  so 
completely,  and  lesions  of  the  islands  appeared  to  be 
less  widespread. 

Since  the  publication  of  the  observations  recorded 
above,  several  writers  have  described  lesions  of  the 
islands  of  Langerhans  accompanying  diabetes.  Gentes 
has  described  a  case  of  diabetes  with  chronic  interstitial 
pancreatitis  invading  the  islands  of  Langerhans.  Weich- 
selbaum  and  Stangl  studied  the  pancreas  from  eighteen 
cases  of  diabetes,  and  in  a  considerable  number,  not 


264  DISEASE   OF   THE    PANCREAS. 

definitely  stated,  found  the  islands  of  Langerhans  dimin- 
ished in  size  and  irregular  in  shape  ;  the  fibrous  stroma 
within  them  was  thickened,  and  their  cells  were  atroph- 
ied and  contained  small  nuclei  which  stained  homo- 
geneously. These  writers  state  that  in  some  instances 
the  stroma  was  greatly  thickened  and  almost  homoge- 
neous, so  that  the  islands  resembled  degenerate  renal 
glomeruli  ;  hence  it  is  probable  that  they  observed  the 
hyaline  condition  previously  described.  Herzog  has 
studied  three  cases  of  diabetes  in  which  the  islands  of 
Langerhans  were  the  seat  of  marked  sclerotic  changes. 
In  one  case  with  a  severe  type  of  diabetes  interacinar 
islands  were  no  longer  recognizable,  but  throughout  the 
pancreas,  which  was  the  seat  of  a  moderate  interstitial 
inflammation,  occurred  small  round  or  irregular  masses 
of  connective  tissue  corresponding  in  size  and  distribu- 
tion to  these  structures,  of  which  they  doubtless  repre- 
sented the  former  site. 

In  a  child  ten  years  of  age  suffering  with  diabetes 
Schmidt  observed  a  lesion  of  the  islands  of  Langerhans 
characterized  by  both  acute  and  chronic  changes  and 
affecting  only  very  slightly  the  secreting  parenchyma. 
Schmidt  recognized  the  interacinar  and  interlobular  type 
of  chronic  pancreatitis  which  I  had  described,  and  in  two 
instances  found  accompanied  by  diabetes  the  interaci- 
nar lesion  which  implicated  the  islands  of  Langerhans. 
In  another  case  in  which  carcinoma  occupied  the  tail 
of  the  pancreas,  while  the  remainder  of  the  gland  was 


THE    PATHOLOGY    OF    DIABETES    MELLITUS.     265 

the  seat  of  advanced  chronic  inflammation  in  conse- 
quence of  calculi  in  the  duct,  the  islands,  imbeded  in 
dense  stroma  were  the  seat  of  sclerotic  changes  ;  dia- 
betes had  been  present.  In  a  fifth  case  of  chronic  pan- 
creatitis islands  of  Langerhans,  though  often  isolated  in 
dense  stroma,  were  numerous  and  not  invaded  by  the 
inflammatory  process. 

Additional  cases  of  hyaline  degeneration  of  the 
islands  of  Langerhans  with  diabetes  have  been  de- 
scribed by  Wright  and  Joslin,  who  report  two  cases 
with  only  very  slight  alterations  of  the  glandular  acini. 
Herzog  has  described  an  instance  in  which  the  lesion 
was  associated  with  slight  chronic  interstitial  inflamma- 
tion, and  Schmidt  has  described  a  similar  case  in  which 
there  was  no  lesion  of  the  parenchyma. 

Hansemann  alone  among  those  who  in  the  last  few 
years  have  systematically  studied  the  islands  of  Langer- 
hans in  diabetes  reaches  the  conclusion  that  they  have 
no  relationship  to  the  disease.  Hansemann,  it  may  be 
mentioned,  discards  the  now  generally  accepted  view 
that  these  bodies  are  composed  of  epithelial  cells 
having  a  common  origin  with  those  of  the  secreting 
acini,  but  thinks  that  they  are  mesoblastic  structures 
formed  about  dilated  capillaries.  He  never  failed  to 
find  interacinar  islands  in  the  pancreas  from  thirty-four 
cases  of  diabetes  referable  to  severe  lesions  of  the 
gland  ;  where  almost  the  whole  parenchyma  was  de- 
stroyed   they    were    usually  scant    in    number,   though 


266  DISEASE    OF   THE    PANCREAS. 

some  persisted  without  recognizable  alterations.  In 
six  cases  he  found  the  islands  of  Langerhans  invaded 
by  what  he  regards  as  hyaline  connective  tissue,  giving 
an  appearance  similar,  he  states,  to  that  which  I  had 
described,  but  they  were  not  more  changed  than  the 
secreting  parenchyma. 

Hansemann  admits,  however,  that  he  has  not  been  able 
to  find  similar  alterations  in  cases  of  interstitial  pancrea- 
titis unaccompanied  by  diabetes.  Little  significance  can 
be  attached  to  the  fact  that  in  no  case  were  all  of  the 
islands  completely  destroyed.  It  is,  moreover,  not  pos- 
sible to  determine  from  Hansemann' s  statement  in  how 
many  cases  of  pancreatic  diabetes  the  islands  were 
altered,  since  he  dismisses  with  little  comment  those 
in  which  the  islands  were  implicated  in  a  wide-spread 
destruction  of  the  parenchyma. 

Relation  of  Diabetes  to  a  Di^ninuiion  in  the  Nu7nber  of 
Islands  of  Langerhans. — Several  recent  writers  have 
claimed  that  diabetes  may  be  associated  with  diminu- 
tion or  even  entire  absence  of  the  islands  of  Langer- 
hans. Ssobolew  in  a  preliminary  communication  pub- 
lished in  1900  cited  two  cases  of  diabetes  in  which  he 
claimed  that  these  structures  were  wholly  absent,  and  in 
four  of  fifteen  cases  described  several  years  later  he 
failed  to  find  them.  Since  the  secreting  parenchyma 
was  entirely  normal,  he  assumed  that  the  islands  might 
disappear  without  leaving  any  trace.  In  nine  cases  he 
found  the  number  of  islands  diminished.     Schmidt  has 


THE    PATHOLOGY    OF    DIABETES    MELLITUS.     267 

never  failed  to  find  interacinar  islands  and  is  sceptical 
of  Ssobolew's  observations.  Ssobolew  did  not  examine 
sections  from  the  various  parts  of  the  pancreas  and 
failed  to  recognize  the  fact  that  islands  may  be  very 
numerous  in  the  tail  of  the  gland  while  they  may 
be  almost  absent  in  other  parts.  In  single  sections 
I  have  failed  to  discover  these  structures,  but  in  all 
cases  of  diabetes  which  I  have  examined  islands  have 
been  found  in  fair  abundance,  particularly  in  the  tail 
of  the  organ. 

Weichselbaum  and  Stangl  carefully  studied  the  islands 
of  Langerhans  in  the  pancreas  of  diabetics.  They  com- 
pared sections  with  control  specimens  made  from  cor- 
responding parts  of  the  pancreas  obtained  from  individ- 
uals of  the  same  age,  and  reached  the  conclusion  that 
with  diabetes  the  number  of  islands  may  be  diminished  ; 
and  since  the  pancreas  is  almost  always  atrophic,  the 
total  number  of  islands  is  still  further  curtailed.  They 
did  not,  however,  separate  cases  in  which  the  islands 
showed  lesions  from  those  in  which  they  were  appa- 
rently normal. 

In  order  to  definitely  determine  the  number  of  the 
islands,  it  is  essential  to  count  them  in  sections  from 
corresponding  parts  of  the  gland.  When  the  interacinar 
bodies  are  the  seat  of  destructive  lesions,  it  is  obvious  that 
the  number  capable  of  functional  activity  is  diminished, 
but  considerable  interest  attaches  to  those  cases  in  which 
no  lesion  can  be  demonstrated.     In  the  following  cases 


268 


DISEASE    OF   THE    PANCREAS. 


of  this  character  sections  from  three  parts  of  the  gland 
were  examined  (exceptions  are  noted)  and  the  num- 
ber of  islands  in  0.5  square  centimetre  determined. 


No.  of  Case. 

Age  of  Patient, 
years. 

Weight  of 
Pancreas, 
grammes. 

Relative  Numt 

er  of  Islands  of  Langerhans  in 

Table,  p.  250. 

Head. 

Body. 

Tail. 

I 

33 



-    (9) 

•  -    (5) 

— 

3 

II 

25 

-    (7) 

—                       — 

5 

47 

60 

-    (23) 

-    (21)             - 

6 

47 

58 

17 

16 

32 

8 

14 

— 

12 

5 

10 

10 

10 

45 

50 

19 

42 

II 

30 

51 

6 

5 

8 

16 

— 

54-5 

32 

31 

42 

Note. — In  Cases  Nos.  i,  3,  and  5  tissue  was  not  preserved  from  different  parts  of  the  gland, 
and  the  figures  in  parenthesis  represent  the  number  of  interacinar  islands  in  sections  taken  at 
random. 

Comparison  with  the  table  on  page  80  shows  that  the 
above  figures  present  no  constant  departure  from  the 
normal.  In  the  head  and  body  of  the  pancreas  about 
eighteen  islands  occur  in  0.5  square  centimetre  ;  in  the 
tail,  approximately  thirty-two.  A  striking  diminution 
is  seen  in  Cases  No.  8,  and  No.  11,  and  is  particularly 
noteworthy  in  Case  No.  8,  a  child  of  fourteen  years,  in 
whose  pancreas  we  would  expect  the  number  of  islands 
to  be  greater  than  in  that  of  the  adult.  In  this  case  the 
existence  of  hereditary  diabetes  ^  suggests    the  occur- 

^  The  case  is  described  by  Dr.  Pleasants  in  a  paper  on  "  Heredity 
in  Diabetes  Mellitus,  with  a  Report  of  Six  Cases  Occurring  in  a 
Family."     Bulletin  of  the  Johns  Hopkins  Hospital,  1900,  xi.,  325. 


THE    PATHOLOGY    OF    DIABETES   MELLITUS.     269 

rence  of  a  cong^enital  defect  of  the  orland.  In  no  instance, 
therefore,  does  the  appearance  of  the  gland  suggest  a 
condition  of  atrophy,  as  most  writers  assume.  Since 
the  organ  is  normal  in  structure,  it  is  rather  more 
probable  that  a  congenital  deficiency  of  pancreatic  tissue 
has  occurred. 

Since  diabetes  does  not  follow  partial  removal  of  the 
pancreas  in  dogs  when  a  fourth  or  a  fifth  of  the  organ 
remains,  it  seems  probable  that  a  gland  weighing  from 
fifty  to  sixty  grammes,  even  should  the  relative  number 
of  islands  be  small,  would  be  sufficient  to  prevent  dia- 
betes. We  are,  however,  unable  to  estimate  the  effect 
of  prolonged  exertion  on  the  part  of  the  defective  gland 
to  carry  on  functions  necessary  to  normal  metabolism. 
Moreover,  slight,  hardly  recognizable  changes — for  ex- 
ample, arterial  sclerosis — may  at  some  period  of  life  be 
sufficient  to  overtopple  the  equilibrium  heretofore  pre- 
served by  the  overworked  gland. 

In  the  series  of  cases  included  in  the  foregoing  table, 
the  pancreas,  though  small,  showed  no  noteworthy 
deviation  from  the  normal  gross  or  histological  struc- 
ture. While  diminution  in  the  size  of  the  gland, 
toofether  with  absolute  and  relative  diminution  in  the 
number  of  interacinar  islands,  may  occasionally  explain 
the  occurrence  of  diabetes,  with  our  present  knowledge 
it  is  unjustifiable  to  assume  the  existence  of  such  func- 
tional deficiency  when  no  lesion  can  be  demonstrated  by 
the  methods  at  our  disposal. 


270  DISEASE    OF   THE   PANCREAS. 

Relationship  of  Diabetes  to  Organs  other  than  the 
Pa7icreas. — Most  writers  agree  that  cases  of  diabetes 
occur  in  which  no  abnormality  of  the  pancreas  is  demon- 
strable. Case  No.  10,  in  which  the  normal  pancreas  of 
a  child  ten  years  old  weighed  forty-five  grammes,  may 
serve  as  an  example.  The  existence  of  such  cases,  how- 
ever, does  not  weaken  the  evidence  in  favor  of  the  pan- 
creatic origin  of  the  disease  in  other  instances,  for  abun- 
dant experimentation  has  demonstrated  the  complexity 
of  carbohydrate  metabolism  and  has  shown  that  the  cen- 
tral nervous  system  and  the  liver  exert  an  important 
influence  in  regulating  the  amount  of  sugar  in  the 
blood,  while  removal  of  an  excess  present  in  the  blood 
is  effected  by  the  kidneys. 

The  experimental  observations  upon  temporary  glyco- 
suria caused  by  changes  in  the  central  nervous  system, 
the  liver,  and  the  kidneys  have  been  followed  by  the 
study  of  human  cases  in  which  glycosuria  or  not  in- 
frequently permanent  diabetes  has  been  associated 
with  lesions  of  these  organs  ;  but  while  the  relation- 
ship of  the  pancreas  to  diabetes  has  been  very 
thoroughly  established  both  by  experimentation  and 
observation,  the  relationship  of  lesions  affecting  other 
organs  is  much  more  obscure.  Moreover,  diabetes  has 
been  found  to  accompany  certain  relatively  uncommon 
diseases — for  example,  exophthalmic  goitre  and  acro- 
megaly— with  such  frequency  that  the  association  cannot 
be  regarded  as  accidental.     In  some  instances  where 


THE   PATHOLOGY    OF    DIABETES    MELLITUS.     271 

diabetes  has  been  supposed  to  be  the  obscure  result  of 
a  condition  recognizable  during  life,  it  is  in  reality  second- 
ary to  a  lesion  of  the  pancreas  the  existence  of  which 
is  not  recognizable  unless  an  autopsy  is  performed. 

Arterial  sclerosis,  as  is  well  known,  is  present  in  a 
large  proportion  of  diabetics,  and  diabetic  gangrene  is 
referable,  in  many  cases  at  least,  to  implication  of  the 
arteries  supplying  the  extremities,  Grube  found  arte- 
rial sclerosis  in  sixty-six  of  one  hundred  and  seventy- 
seven  cases  of  diabetes,  G,  Hoppe-Seyler  and  Fleiner 
have  described  cases  of  diabetes  in  which  chronic  inter- 
stitial inflammation  of  the  organ  accompanied  general 
arterial  sclerosis.  Case  XX,  of  my  series  illustrates 
this  condition  ;  here  both  chronic  interacinar  pancrea- 
titis and  gangrene  of  the  leg  appear  to  be  the  result 
of  advanced  arterial  sclerosis.  In  two  of  my  cases, 
including  that  just  mentioned,  arterial  sclerosis  has 
been  recognizable  in  sections  from  the  pancreas,  the 
small  arteries  of  the  organ  showing  thickening  of  the 
intima  or  degenerative  changes  in  the  media.  It  is  not 
improbable  that  arterial  sclerosis  produces  diabetes,  or 
at  least  favors  its  occurrence  by  altering  the  nutrition 
of  the  pancreas. 

There  is,  I  believe,  sufficient  evidence  to  demonstrate 
that  diabetes  accompanying  cirrhosis  of  the  liver  is,  in 
the  majority  of  cases  at  least,  the  result  of  chronic  inter- 
stitial pancreatitis  ;  chronic  inflammation  of  the  liver  and 
pancreas    coexist  as   the   result  of  the   same   primary 


272 


DISEASE    OF   THE   PANCREAS. 


etiological  factor, — for  example,  alcohol.  Diabetes  with 
cirrhosis  is  a  well-recognized  condition,  and  numerous 
cases  are  recorded  ;  among  one  hundred  and  twenty- 
eight  cases  of  diabetes  observed  in  hospital  clinics  by 
Naunyn,  seven  were  accompanied  by  cirrhosis,  but  in 
his  private  practice,  among  one  hundred  and  fifty-eight 
cases,  twenty-two  were  with  cirrhosis.  I  have  studied 
three  cases  in  which  the  two  conditions  were  associated, 
and  in  all  the  pancreas  was  the  seat  of  chronic  interac- 
inar  inflammation  invading  the  islands  of  Langerhans. 
In  cases  of  diabetes  accompanying  cirrhosis  described 
with  autopsy  report  by  Dieckhoff  and  by  Pusinelli, 
the  pancreas  showed  chronic  inflammatory  changes. 

The  relationship  of  cirrhosis  of  the  liver  to  chronic 
interstitial  pancreatitis  has  already  been  discussed.  The 
condition  known  as  hsemochromatosis,  to  be  described 
later,  offers  an  excellent  illustration  of  the  dependence 
of  cirrhosis  of  the  liver  and  chronic  pancreatitis  upon 
the  same  etiological  factors  ;  in  this  condition  diabetes 
occurs  as  a  terminal  event,  when  the  pancreatic  inflam- 
mation which  is  of  the  interacinar  type  has  reached  a 
moderate  grade  of  severity. 

The  possibility  suggests  itself  that  the  alimentary 
glycosuria  inconstantly  observed  with  cirrhosis  of  the 
liver  by  Colrat  and  Couturier,  Krause  and  Ludwig,  and 
others,  may  be  the  result  of  slight  coexisting  alterations 
of  the  pancreas,  for  Wille  has  shown  that  lesions  of  the 
gland  accompanying,   for  example,  primary  carcinoma 


THE    PATHOLOGY   OF    DIABETES    MELLITUS.     273 

or  carcinoma  of  the  stomach  invading  the  pancreas, 
may  be  associated  with  alimentary  glycosuria. 

Added  interest  is  attached  to  the  remarkable  associa- 
tion of  acromegaly  and  diabetes  by  the  fact  that  the 
former  disease  is  not  infrequently  accompanied  by 
induration  of  the  interstitial  tissue  of  the  pancreas. 
Hansemann  found  diabetes  present  in  twelve  of  ninety- 
seven  reported  cases  of  acromegaly,  a  case  of  his  own 
included.  More  recently  Schlesinger  has  described 
three  cases  of  acromegaly,  one  associated  with  diabetes, 
a  second  accompanied  by  transient  glycosuria,  and  a 
third  with  alimentary  glycosuria.  Frankel,  Stadelmann, 
and  Benda  among  four  cases  of  acromegaly  observed 
one  with  temporary  glycosuria  and  a  second  with 
diabetes. 

A  review  of  cases  described  with  autopsy  reports 
shows  that  chronic  pancreatitis  has  been  repeatedly 
observed  in  association  with  acromegaly  ;  the  probabil- 
ity is,  therefore,  strong  that  diabetes  is  referable  to 
this  lesion,  even  though  cases  with  diabetes  have  been 
described  in  which  it  is  claimed  there  was  no  lesion  of 
the  gland.  Dallemange  found  chronic  interstitial  inflam- 
mation of  the  gland  in  two  cases  of  acromegaly,  one 
of  which  was  associated  with  diabetes.  In  the  case 
of  acromegaly  with  diabetes  described  by  Hansemann 
chronic  pancreatitis  was  present.  In  a  case  with  glyco- 
suria, recorded  by  Frankel,  Stadelmann,  and  Benda,  the 
pancreas  showed  a  condition  described  as  nodular  hyper- 


2  74  DISEASE    OF   THE   PANCREAS. 

trophy,  while  in  a  second  with  diabetes  no  lesion  was 
noted,  but  here  no  microscopic  examination  was  made. 
In  one  case  of  acromegaly  without  diabetes,  described 
by  the  writers  just  named,  and  in  a  similar  case  de- 
scribed by  Mitchell  and  Le  Count,  chronic  inflammation 
of  the  pancreas  was  demonstrable.  Pineles  found  at 
autopsy  upon  a  case  of  acromegaly  with  persistent 
diabetes  purulent  pancreatitis  with  fat  necrosis,  but 
the  presence  of  pre-existing  chronic  inflammation  can 
only  be  suspected.  The  cases  cited  indicate  that  indu- 
ration presumably  analogous  to  that  which  acromegaly 
causes  elsewhere  occurs  also  in  the  pancreas  and  where 
sufficiently  advanced  produces  glycosuria  or  even  per- 
manent diabetes. 

The  relationship  of  diabetes  to  the  central  nervous 
system  has  been  much  discussed.  The  influence  of  the 
nervous  system  upon  the  excretion  of  sugar  is  shown  by 
Claude  Bernard's  puncture  of  the  floor  of  the  fourth 
ventricle  and  by  other  experimental  injuries  to  the 
central  nervous  system.  That  glycosuria  frequently 
follows  injuries  to  the  brain  is  shown  by  the  statistics  of 
Higgins  and  Ogden,  who  found  glycosuria  in  9.3  per 
cent,  of  two  hundred  and  twelve  cases  of  traumatism 
affecting  the  head,  while  of  forty-five  cases  in  which 
the  skull  was  fractured  glycosuria  followed  in  21.9  per 
cent.  Instances  of  permanent  diabetes  following  cere- 
bral lesions  are  recorded,  but  the  relationship  of  the  dis- 
ease to  the  injury  is  doubtful.      Diabetes  is  occasionally 


THE   PATHOLOGY    OF    DIABETES   MELLITUS.     275 

associated  with  tabes  dorsalis  or  with  muhiple  sclerosis, 
and  has  been  regarded  as  secondary  to  the  nervous 
lesions. 

Of  greater  interest,  in  view  of  the  experiments  of 
Claude  Bernard,  is  the  recorded  association  of  lesions 
of  the  medulla  with  diabetes.  In  cases  of  multiple 
sclerosis  described  by  Weichselbaum  and  by  Richardiere 
plaques  occupied  the  floor  of  the  fourth  ventricle.  Re- 
markable instances  in  which  small  tumors  have  en- 
croached upon  the  floor  of  the  fourth  ventricle  are 
recorded  by  Levrat-Perroton,  von  Recklinghausen,  and 
Verron.  In  a  case  recorded  by  Michael  a  cysticercus 
occupied  the  fourth  ventricle.  Even  though  the  great 
rarity  of  such  conditions  be  considered,  it  is  not  im- 
possible that  they  may  act  as  exciting  causes  in  the 
production  of  diabetes. 

Glycosuria  following  the  administration  of  phloridzin 
has  been  mentioned.  Since  most  observers  are  agreed 
that  with  this  form  of  glycosuria  the  amount  of  sugar  in 
the  blood  is  not  increased,  the  possibility  has  suggested 
itself  that  the  kidneys  are  so  altered  that  they  admit  the 
passage  of  the  sugar  normally  present  in  the  blood. 
The  occurrence  of  an  analogous  renal  diabetes  in  human 
beings  has  been  suspected.  Klemperer  has  described  a 
case  of  diabetes  associated  with  nephritis.  The  amount 
of  suofar  in  the  blood  was  not  orreater  than  normal,  and 
after  the  administration  of  one  hundred  and  fifty  grammes 
of  glucose  the  amount  of  sugar  in  the  urine  and  in  the 


276  DISEASE    OF   THE   PANCREAS. 

blood  was  not  increased.  Cases  in  which  pre-existing 
nephritis  has  been  associated  with  diabetes  are  cited  by 
Naunyn  and  by  Eger,  but  since  they  may  be  referable 
to  the  more  or  less  accidental  co-existence  of  these  two 
conditions,  they  do  not  furnish  strong  evidence  that  gly- 
cosuria is  dependent  upon  the  renal  lesion. 

Richter  has  studied  experimentally  the  relationship  of 
glycosuria  to  lesions  of  the  kidney.  Small  doses  of  cor- 
rosive sublimate  injected  into  the  venous  circulation  of 
rabbits  cause  not  only  albuminuria,  but  glycosuria  as 
well.  Very  small  doses,  however,  may  cause  glycosu- 
ria, but  no  albuminuria  ;  and  since  the  amount  of  sugar 
in  the  blood  is  found  to  be  increased,  Richter  does  not 
think  that  the  glycosuria  should  be  attributed  to  altera- 
tions of  the  kidneys.  Glycosuria  produced  by  phlorid- 
zin  is,  moreover,  diminished  or  prevented  if  a  lesion  of 
the  kidney  is  produced  by  the  administration  of  aloin  or 
potassium  chromate.  Elbinger  and  Selig  rendered  dogs 
diabetic  and  then  administered  cantharadin  in  order 
to  injure  the  kidneys.  They  found  that  glycosuria 
diminished  with  the  onset  of  renal  changes.  Lesions  of 
the  kidney  in  animals  appear  to  retard  rather  than 
favor  the  excretion  of  sugar,  while  it  has  been  ob- 
served that  in  cases  of  diabetes  glycosuria  not  infre- 
quently diminishes  with  the  appearance  of  albuminuria. 
True  renal  diabetes  may  occur  as  the  result  perhaps 
of  some  peculiar  injury  to  the  kidney,  but  its  existence 
has  not  as  yet  been  demonstrated. 


THE    PATHOLOGY    OF    DIABETES    MELLITUS.     277 

The  association  of  diabetes  with  diseases  of  certain 
ductless  glands  is  of  considerable  interest.  Exophthal- 
mic goitre  has  been  not  infrequently  accompanied  by 
diabetes  ;  and  Hannemann,  who  has  made  a  careful 
survey  of  the  literature,  has  been  able  to  collect  fifteen 
cases  in  which  the  two  diseases  were  associated.  At 
least  a  dozen  writers  have  observed  temporary  glyco- 
suria with  exophthalmic  goitre.  Alimentary  glycosuria 
with  exophthalmic  goitre  was  first  observed  by  Kraus 
and  Ludwig ;  later,  Chvostek  reached  the  conclusion 
that  it  occurs  in  sixty-nine  per  cent,  of  all  cases,  but 
Strauss  observed  glycosuria  after  the  administration 
of  one  hundred  grammes  of  grape  sugar  in  only  three 
of  nineteen  cases.  Glycosuria  following  the  therapeutic 
use  of  thyroid  extract  has  been  observed.  In  none  of 
the  cases  of  diabetes  associated  with  exophthalmic  goitre 
has  the  condition  of  the  pancreas  been  studied. 

The  claim  has  been  recently  advanced  that  the  adrenal 
gland  exerts  an  influence  upon  carbohydrate  metabol- 
ism. Blum  has  produced  temporary  glycosuria  by  in- 
jecting extracts  made  from  the  adrenal  into  the  subcuta- 
neous tissue  or  veins  of  a  variety  of  animals.  The 
extract  produces  very  grave  toxic  symptoms  and  not 
infrequently  death,  so  that  it  is  by  no  means  improbable 
that  the  substance  acts  upon  organs  which  control  car- 
bohydrate metabolism.  Herter  and  Richards  have 
found  that  if  the  extract  known  as  adrenalin  be  injected 
into   the   peritoneal  cavity  glycosuria  is   of  greater  in- 


278  DISEASE    OF   THE    PANCREAS. 

tensity  than  after  subcutaneous  injection.  By  merely 
painting  the  surface  of  the  pancreas  with  the  extract 
a  similar  effect  is  produced. 

Summary  and  Conclusion. — The  occurrence  of  glyco- 
suria and  diabetes  in  association  with  lesions  of  the 
ner\'ous  system,  with  disease  of  certain  ductless  glands, 
and  after  the  administration  of  certain  toxic  substances, 
indicates  the  complexity  of  carbohydrate  metabolism. 
Normal  assimilation  of  sugar  doubtless  depends  upon 
a  variety  of  factors,  among  which  integrity  of  the  pan- 
creas, though  very  important,  does  not  stand  alone,  and 
disturbances  of  carbohydrate  metabolism  may  be  the 
result  of  conditions  affecting  other  organs.  Hence 
the  occurrence  of  diabetes  unaccompanied  by  altera- 
tions of  the  pancreas  is  not  surprising  and  furnishes  no 
evidence  to  disprove  the  relationship  of  the  disease  to 
o-rave  lesions  of  the   o-land.       Nevertheless   the   occur- 

o  o 

rence  of  pancreatic  diabetes  is  much  more  frequent 
than  has  been  supposed.  The  foregoing,  moreover, 
has  shown  that  in  many  instances,  at  least,  diabetes, 
associated  with  a  variety  of  conditions,  arterial  sclerosis, 
cirrhosis  of  the  liver,  haemochromatosis,  and  acromegaly, 
is  secondary  to  a  lesion  of  the  pancreas  accompanying 
these  diseases.  Arterial  sclerosis,  haemochromatosis, 
and  acromegaly  produce  chronic  interstitial  inflamma- 
tion of  the  pancreas,  while  cirrhosis  of  the  liver 
accompanies  chronic  pancreatitis,  because  both  are  the 
result  of  the  same  etiological  factor.      The  relationship. 


THE    PATHOLOGY    OF    DIABETES    MELLITUS. 


279 


of  the  nervous  system,  of  the  kidneys,  and  of  the 
thyroid  and  adrenal  glands  to  diabetes  is  more  obscure. 

In  order  to  accurately  determine  the  frequency  of  pan- 
creatic diabetes,  the  relative  frequency  of  accompanying 
lesions  of  the  pancreas,  and  the  relationship  of  the 
eland  to  alterations  in  other  organs  it  is  essential  that 
a  considerable  number  of  cases  be  studied  with  such 
care  that  it  is  possible  to  determine  not  only  the  exist- 
ence of  acquired  lesions  but  the  occurrence  of  congeni- 
tal anomalies,  causing,  it  may  be,  functional  insuffi- 
ciency. In  every  case  of  diabetes  the  weight  of  the 
gland  should  be  determined  ;  sections  should  be  exam- 
ined from  the  head,  mid-part  of  the  body,  and  splenic 
extremity  of  the  gland,  and  the  character  and  extent  of 
existing  lesions  determined.  In  the  absence  of  patho- 
logical changes  the  number  of  the  islands  in  various 
parts  of  the  gland  should  be  determined  by  actual 
count,  and  a  possible  diminution  of  their  relative  and 
absolute  number  estimated. 

The  following  important  facts  are,  I  believe,  estab- 
lished :  (i)  In  considerably  more  than  half  of  all  cases 
diabetes  is  the  result  of  a  destructive  lesion  of  the 
pancreas.  (2 )  Where  diabetes  is  the  result  of  pancreatic 
disease,  injury  to  the  islands  of  Langerhans  is  responsi- 
ble for  the  disturbance  of  carbohydrate  metabolism,  since 
that  influence  which  the  normal  pancreas  exerts  upon  the 
assimilation  of  sugar  is  a  function  of  these  structures. 
(3)  The  most  common  lesions  which  injure  the  islands  of 


28o  DISEASE    OF   THE   PANCREAS. 

Langerhans  are  chronic  interstitial  inflammation  of  the 
interacinar  type  and  hyaline  degeneration.  Chronic  in- 
terstitial inflammation  may  be  the  result  of  general  arte- 
rial sclerosis  or  of  toxic  substances, — for  example,  alco- 
hol causing  chronic  inflammation  of  both  the  liver  and 
pancreas.  The  islands  of  Langerhans  show  a  special 
tendency  to  undergo  hyaline  degeneration,  but  the  cause 
of  this  lesion  is  obscure.  (4)  Other  lesions  of  the  pan- 
creas do  not  exhibit  a  tendency  to  select  the  islands  of 
Langerhans,  but  produce  diabetes  because  they  destroy 
the  interacinar  islands  along  with  the  secreting  paren- 
chyma. Such  is  true  of  very  advanced  interlobular  pan- 
creatitis which  follows  duct-obstruction,  the  invasion  of 
malignant  tumors,  and  the  necrosis  of  acute  inflammatory 
lesions. 


CHAPTER    XII. 

HEMOCHROMATOSIS   AND    BRONZED    DIABETES. 

The  relationship  between  diabetes  and  lesions  of  the 
pancreas  is  well  illustrated  by  the  disease  known  as 
haemochromatosis,  a  disturbance  of  iron  metabolism, 
which,  though  rare,  has  excited  much  interest  on  ac- 
count of  its  remarkable  character  and  obscure  patho- 
genesis. Its  identity  with  "  diabete  bronze" — or  the 
diabetes  with  pigmentation  and  cirrhosis  of  French 
writers — is  now  recognizable. 

Under  the  desio^nation  "haemochromatosis,"  von 
Recklinghausen  in  1889  described  a  condition  of  pig- 
mentation affecting  various  organs.  Brown  pigment, 
which  he  thought  was  derived  from  the  haemoglobin  of 
the  blood,  is  deposited  within  certain  tissues  and  gives 
to  them  macroscopic  pigmentation. 

The  anatomical  picture  of  generalized  pigmentation 
drawn  by  von  Recklinghausen  is  very  clearly  defined. 
Most  of  the  glands  of  the  body  assume  a  deep  brown 
color,  and  within  their  secreting  cells  are  found  reddish- 
yellow  or  ochre-colored  granules.  Microchemical  reac- 
tions prove  that  this  pigment  contains  iron.  In  the  liver 
pigment  is  present  in  the  parenchymatous  cells  and 
in  Kupffer's  cells.  A  second  kind  of  pigment,  distin- 
guishable from  the  first  by  its  finer  granules  of  pure 


282  DISEASE    OF   THE    PANCREAS. 

yellow  color,  is  found  in  the  smooth  muscle-cells  of  the 
stomach  and  intestines,  of  the  blood-  and  lymph-vessels, 
rarely  in  the  muscle  of  the  urinary  bladder,  ureters, 
and  vas  deferens.  It  also  exists  in  the  connective-tissue 
cells  of  certain  localities, — for  example,  Glisson's  cap- 
sule, the  splenic  trabeculse,  and  the  sheaths  of  blood-ves- 
sels. This  second  pigment  does  not  give  the  reactions 
characteristic  of  iron.  Von  Recklinghausen  called  the 
iron-containing  pigment  "  haemosiderin,"  the  iron-free 
pigment  "haemofuscin."  The  use  of  these  names  does 
not  necessarily  imply  that  we  have  means  of  iden- 
tifying the  substances  as  definite  chemical  compounds 
or  that  we  can  recognize  them  when  they  occur  in 
other  situations.  Von  Recklinghausen  thought  that 
haemofuscin,  as  well  as  the  iron-containing  hsemosiderin, 
was  derived  from  haemoglobin.  In  his  cases  of  gener- 
alized pigmentation  there  was  an  associated  cirrhosis  of 
the  liver. 

Von  Recklinghausen  studied  twelve  cases  which  he 
regarded  as  examples  of  local  and  general  haemochro- 
matosis.  He  defined  haemochromatosis  as  a  condition 
of  pathological  pigmentation  due  to  the  deposition  of 
pigment  derived  from  the  blood. 

There  is,  however,  a  local  condition  which  has  been 
identified  with  haemochromatosis  by  several  observers  ; 
pigmentation  of  the  intestine  caused  by  deposition  of 
fine  yellow  granules  in  the  smooth  muscle-cells  has  been 
carefully  studied  by  Goebel  and  others.     In  adults  mod- 


HEMOCHROMATOSIS    AND    BRONZED    DIABETES.      283 

erate  pigmentation  is  almost  constant,  and  the  amount 
of  pigment  present  bears  a  relationship  to  the  age  of  the 
individual,  so  that  with  increasing  age  there  is  an  in- 
creased pigment  deposition.  With  wasting  diseases— 
for  example,  tuberculosis  and  carcinomatosis — there  may 
be  an  accumulation  equal  to  that  present  in  advanced 
age.  In  sixteen  of  one  hundred  bodies  studied  by 
Goebel  the  pigment  deposit  was  of  sufficient  magnitude 
to  cause  macroscopic  discoloration,  characterized  by 
him  as  rust  brown.  This  accumulation  of  pigment  with- 
in the  smooth  muscle-cells  of  the  intestine  is  apparently 
an  accentuation  of  a  physiological  process  much  more 
closely  related  to  brown  atrophy  of  the  heart  than  to 
ofeneral  hsemochromatosis. 

Von  Recklinghausen's  description  defines  a  con- 
dition presenting  no  close  similarity  to  any  form  of 
local  pigmentation  with  which  we  are  familiar.  The  im- 
portant features  of  this  description  are:  (i)  The  pre- 
sence in  the  epithelial  cells  of  various  glands,  notably 
the  liver  and  pancreas,  of  an  iron-containing  pigment. 
(2)  The  presence  of  an  iron-free  pigment  in  smooth 
muscle-cells  of  the  o-astro-intestinal  tract,  and  of  the 
blood-  and  lymph-vesseis,  and  in  certain  connective-tis- 
sue cells.  (3)  The  association  of  cirrhosis  of  the  liver 
with  pigmentation.  To  this  condition,  apparently  a  dis- 
tinct pathological  entity,  the  term  haemochromatosis 
should  be  limited. 

Prior  to  von  Recklinghausen's  publication  several  ob- 


284  DISEASE    OF    THE    PANCREAS. 

servers  had  studied  cases  of  wide-spread  pigmentation. 
Quincke  in  1877  observed  with  anaemia  a  deposition 
of  iron  in  various  organs,  notably  in  the  Hver  and 
spleen,  and  in  one  instance  found  macroscopic  pig- 
mentation of  the  liver  and  pancreas  as  a  result. 
Tillmanns  described  broAvn  pigmentation  of  the  liver, 
of  the  abdominal  lymphatic  glands,  and  in  less  degree 
of  the  spleen  and  pancreas,  in  a  man  who  two  months 
before  death  had  sustained  a  fracture  of  the  pelvis,  and. 
the  observer  thought,  a  contusion  of  the  liver.  Hinden- 
lang  observed  in  association  with  morbus  maculosus 
Werlhofii  pigmentation  of  the  glands  of  the  body,  par- 
ticularly the  liver,  which  was  slightly  cirrhotic,  and  the 
pancreas,  and  in  these  organs  found  a  pigment  corre- 
sponding to  that  Avhich  von  Recklinghausen  subse- 
quently described  as  haemosiderin. 

Hintze  has  described  six  cases  which  he  regards 
as  examples  of  hsemochromatosis,  but  only  three  agree 
in  detail  with  the  description  which  von  Recklinghausen 
has  given.  Buss  has  described  a  t}^pical  case  of  hsemo- 
chromatosis  associated  with  cirrhosis  of  the  liver  and 
diabetes  mellitus.  Letulle  records  two  cases  and 
Richardiere  one  in  which  with  hypertrophic  cirrhosis 
there  was  pigmentation  of  the  liver,  of  the  pancreas, 
and  of  other  organs.  In  these  cases  pigmentation  of 
the  skin  was  apparently  absent. 

The  following  case  which  occurred  in  the  practice  of 
Dr.  Thomas  Opie  is  an   example  of  the  disease.     Of 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      285 

present  importance  are  the  alterations  of  the  pancreas 
which,  though  unassociated  with  diabetes,  are  such  as 
might  cause  the  condition  were  they  more  advanced. 

Case  XXXII. — The  patient,  male,  white,  aged  fifty-five  years, 
though  never  very  robust,  had  enjoyed  fairly  good  health.  There 
was  no  history  of  alcoholic  excess.  For  several  months  he  had  re- 
sided in  Porto  Rico,  and  until  six  or  seven  weeks  before  his  death 
was  able  to  continue  his  work  of  surveying.  The  onset  of  his  fatal 
illness  occurred  with  symptoms  indicative  of  typhoid  fever.  When 
first  seen,  two  weeks  later,  he  was  evidently  very  ill.  There  was  ele- 
vation of  temperature  and  rose-spots  were  present  upon  the  abdomen. 
Deep  pigmentation  of  the  skin  attracted  immediate  attention  and 
marked  universal  bronzing  suggested  Addison's  disease.  Jaundice 
was  not  present.  The  urine  at  no  time  during  the  period  of  obser- 
vation contained  sugar  ;  the  first  examination  was  made  four  weeks 
before  death.  Three  days  before  death  the  urine  was  clear,  of  deep 
amber  color,  and  contained  neither  sugar  nor  albumin.  The  blood- 
serum  caused  the  agglutination  of  the  typhoid  bacillus.  Death 
occurred  with  increasing  weakness. 

Autopsy. — The  body  is  that  of  a  very  thin,  sparely  built  man. 
The  skin  over  the  entire  body  shows  deep  pigmentation  of  a  bronzed 
metallic  hue,  most  marked  upon  the  back  of  the  hands,  about  the 
nipples,  and  upon  the  penis,  Avhere  just  above  the  corona  the  skin 
has  a  dark  brown  color.  The  parietal  peritoneum,  as  well  as  that 
of  the  intestines,  shows  a  varying  degree  of  bluish  discolora- 
tion. 

The  muscle  of  the  heart  has  a  yellowish-brown  color,  and  is  soft 
and  flabby.  Upon  the  surface  of  the  right  lung  are  several  promi- 
nent areas  over  which  the  pleura  is  dulled ;  the  tissue  below  is  firmly 
consolidated.     The  bronchi  are  intensely  injected. 

The  liver  weighs  2270  grammes.     The  surface  has  a  deep  reddish- 


286  DISEASE    OF   THE    PANCREAS. 

brown  color  of  peculiar  character,  resembling  that  of  iron-rust.  The 
surface  of  the  left  lobe,  more  markedly  than  that  of  the  right,  is  super- 
ficially nodular  and  puckered,  presenting  in  moderate  degree  the 
appearance  of  a  hob -nail  liver.  On  section  islands  of  lighter  brown 
parenchyma,  representing  one  or  several  lobules,  are  surrounded  by 
fibrous  stroma  of  a  deeper  brown  color.  Sparsely  scattered  are 
opaque,  yellowish-white  areas,  often  i .  5  millimetres  across. 

The  spleen,  weighing  700  grammes,  is  soft,  and  on  section  the  almost 
diffluent  pulp  has  a  deep  red  color.  The  mucous  membrane  of  the 
stomach  shows  everywhere  a  deep  greenish-black  discoloration,  evi- 
dently not  due  to  post-mortem  change.  Along  the  lesser  curvature 
there  are  a  few  areas  of  relatively  normal  yellowish-white  appear- 
ance, but  elsewhere  the  pigmentation  is  uniform.  The  duodenum 
has  a  greenish-black  discoloration  almost  equal  in  intensity  to  that 
of  the  stomach.  The  jejunum  is  less  markedly  pigmented  than  the 
duodenum,  while  the  ileum  is  of  even  lighter  color,  though  still  pre- 
serving a  greenish-gray  tint.  Throughout  the  lower  part  of  the 
ileum,  usually  upon  the  Peyer's  patches,  are  small  round  or  slightly 
irregular  ulcers  with  sharp  edges  and  clean  base,  in  which  are  occa- 
sionally seen  exposed  fibres  of  the  circular  muscle-coat.  The  colon 
exhibits  moderate  greenish-gray  discoloration. 

The  pancreas  weighs  170  grammes.  The  organ  is  of  large  size, 
measuring  sixteen  centimetres  in  length,  and  is  very  firm  in  consist- 
ence. On  section  the  cut  surface  has  a  uniform  deep  chocolate -brown 
color.  The  capsule  contains  much  fat,  and  extending  inward  from  it 
are  septa  of  adipose  and  fibrous  tissue. 

The  cortex  of  the  kidneys,  of  an  average  thickness  of  seven  milli- 
metres, has  a  red,  cloudy  appearance.  On  section  the  testicles  have  a 
light  brown  tint.  In  the  retroperitoneal  tissue  near  the  hepatic  vein, 
behind  the  stomach,  above  and  below  the  pancreas,  and  on  either 
side  of  the  aorta  as  low  down  as  its  bifurcation,  are  enlarged,  mod- 
erately firm   lymphatic  glands.      On  section   they  have  a  uniform. 


HEMOCHROMATOSIS   AND    BRONZED    DIABETES.      287 

brilliant  orange-yellow  surface.  In  the  gastro-hepatic  omentum  are 
enlarged  glands  of  a  similar  nature. 

Anatomical  Diagnosis.  — Typhoid  fever ;  ulcers  in  the  ileum  ; 
acute  splenic  tumor ;  cloudy  degeneration  of  the  kidneys ;  broncho- 
pneumonia. Hsemochromatosis ;  pigmentation  of  the  liver,  pan- 
creas, heart,  stomach,  intestine,  peritoneum,  lymphatic  glands,  skin, 
and  testicles ;  cirrhosis  of  the  liver  ;  chronic  interstitial  pancreatitis. 

Histological  Examination. — The  organs  which  show  the  most 
marked  pigmentation  are  the  liver,  pancreas,  heart,  and  gastro- 
intestinal canal. 

Advanced  cirrhosis  of  the  hver  is  indicated  by  the 
presence  of  wide  bands  of  fibrous  tissue  occupying  from 
one-half  to  one-third  of  the  area  of  the  cut  surface  and 
separating  the  parenchyma  into  islands  which  repre- 
sent one  or  several  lobules.  These  septa,  which  are 
densely  fibrous  and  in  general  poor  in  cells,  surround 
both  the  portal  spaces  and  the  sublobular  veins.  A 
very  conspicuous  feature  of  the  histological  picture  is 
the  immense  amount  of  yellowish-brown  pigment  pres- 
ent in  the  parenchymatous  cells.  It  is  deposited  in 
the  form  of  refractive,  relatively  coarse  granules,  of 
variable  size.  The  endothelial  cells  of  the  capillaries 
and  Kupffer's  cells  contain  granules  of  similar  char- 
acter. Pigment  is  even  more  abundant  in  the  newly- 
formed  fibrous  tissue.  Here  it  exists  in  part  as  fine 
granules  within  spindle-shaped  cells,  but  the  greater 
quantity  is  not  contained  in  cells.  While  this  extra- 
cellular pigment  is  of  the  same  yellowish-brown  color 
as   that  within   the   cells,   the  individual   particles  vary 


288  DISEASE    OF   THE   PANCREAS. 

greatly  in  size,  globules  being  often  found'  two  or  three 
times  as  large  as  a  red  corpuscle.  This  yellowish- 
brown  pigment  gives  the  microchemical  reactions  char- 
acteristic of  iron. 

There  is  present  a  second  less  conspicuous  variety 
of  pigment,  differing  from  that  already  described  both 
in  situation  and  in  morphology.  In  certain  smooth 
muscle  and  connective-tissue  cells  situated  in  the  media 
and  adventitia  of  both  veins  and  arteries  are  deposited 
fine,  pale  yellow  granules  of  almost  uniform  size. 
This  pigment  does  not  give  the  microchemical  reac- 
tions of  iron,  being  unchanged  by  potassium  ferrocya- 
nide  and  hydrochloric  acid.  In  sections  stained  with 
methylene  blue  these  granules  take  a  blue,  often  bluish- 
black,  color  and  become  very  conspicuous.  This  fact 
has  been  observed  by  Buss. 

Interstitial  tissue  of  the  pancreas  is  much  increased  ; 
in  many  places  it  defines  the  lobules,  but,  as  a  rule,  it 
is  diffusely  distributed,  occurring  as  irregular  masses 
and  strands  separating  small  groups  of  acini  or  indi- 
vidual acini.  Yellowish-brown  pigment,  giving  the  mi- 
crochemical reactions  of  iron,  is  abundant  both  in  the 
o-landular  cells  and  in  the  interstitial  tissue.  The  cells  of 
the  acini  contain  this  pigment  in  varying  amount ;  here 
and  there  are  seen  acini  the  cells  of  which  are  distended 
with  pigment  granules,  their  protoplasm  being  almost 
entirely  replaced.  Such  cells  often  show  evidence  of 
degeneration  ;    at  times  the  nucleus  has  an  irregular 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      289 

outline,  and  stains  very  palely,  w^hile  in  many  instances 
no  nucleus  is  demonstrable.  The  fibrous  tissue  replac- 
ing the  disintegrated  cells  contains  free  granules  of 
pigment,  which  are  larger  and  more  globular  than  those 
within  the  cells. 

Islands  of  Langerhans  are  fairly  abundant  throughout 
the  orean,  but  are  most  numerous  in  sections  from  the 
tail.  They  are  constantly  surrounded  by  a  small  area 
of  fibrous  tissue  containing  pigment  in  considerable 
quantity.  Embedded  in  stroma,  they  no  longer  possess 
a  regular  round  or  oval  outline,  but  are  irregular  in 
shape  and  are  penetrated  by  thickened  fibrous  strands 
which  follow  the  capillary  vessels.  The  cells,  forming 
compact  columns,  contain  numerous  granules  of  pig- 
ment, which,  when  least  abundant,  are  situated  in  the 
part  of  the  cell  most  distant  from  the  capillaries,  and 
hence  tend  to  occupy  the  mid-line  of  the  cell-columns. 
The  cells  of  the  interacinar  islands  usually  contain  much 
more  pigment  than  those  of  the  adjacent  acini.  In 
preparations  hardened  in  Fleming's  solution  fat  can  be 
found  in  many  of  the  secreting  cells,  but  is  constantly 
present  in  the  cells  of  the  interacinar  islets. 

Pigment  deposition  and  the  associated  histological 
lesions  in  the  skin,  gastro-intestinal  tract,  heart,  spleen, 
kidneys,  adrenals,  and  lymphatic  glands,  though  of 
considerable  interest,  are  not  pertinent  to  the  present 
study,  and  their  description  will  be  omitted. 

Bronzed  Diabetes. — A  condition  closely  related  to  the 

19 


290  DISEASE   OF   THE    PANCREAS. 

haemochromatosis  of  von  Reckling-hausen  has  been 
studied  particularly  by  French  writers.  In  1882  Hanot 
and  Chauffard  described  two  cases  of  diabetes  mellitus 
associated  clinically  with  hypertrophic  cirrhosis  of  the 
liver  and  bronze-like  pigmentation  of  the  skin.  At 
autopsy  upon  the  first  of  these  cases  was  found  cirrhosis 
of  the  liver,  characterized  by  wide  bands  of  connective  tis- 
sue, and  in  the  hepatic  cells,  as  well  as  in  the  interlobular 
bands,  were  brown  pigment  granules  in  great  quantity. 
In  the  second  case,  more  carefully  studied,  the  liver  and 
pancreas  presented  a  brown  pigmentation  and  were 
the  seat  of  advanced  chronic  interstitial  inflammation, 
both  parenchymatous  cells  and  interstitial  tissue  con- 
taining masses  of  pigment  granules.  The  stomach  and 
duodenum  were  of  a  bluish-black  color,  and  pigment  in 
small  eranules  was  found  below  the  serosa.  Letulle 
several  years  later  reported  two  cases  of  a  similar 
nature.  In  a  second  communication,  Hanot,  in  conjunc- 
tion with  Schachmann,  recorded  a  fifth  case  and  re- 
viewed those  previously  pubhshed.  He  believed  that 
the  obser\^ations  which  had  been  made  established  the 
existence  of  a  new  form  of  cirrhosis — cirj^hose  pigme7i- 
taire  diabetique — and  of  a  new  clinical  condition — diabete 
bronze. 

The  designation  "diabete  bronze"  has  been  in  gen- 
eral accepted,  but  not  without  protest.  Bronzing  of  the 
skin  is  not  a  constant  phenomenon,  and  has  been  found 
absent  in  one  case  of  Letulle,  in  the  case  of  Hanot  and 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      291 

Schachmann,   and  in   a  case  recorded  by  Brault   and 
Galliard. 

In  the  recorded  cases  of  so-called  bronzed  diabetes  the 
symptoms  and  pathological  findings  have  been  very  con- 
stant. Clinically,  the  picture  is  one  of  a  rapidly  fatal 
diabetes  mellitus,  associated  with  cirrhosis  of  the  liver, 
usually  of  the  hypertrophic  variety.  Bronzing  of  the 
skin  is,  as  stated,  not  constant,  but  has  been  present  in 
a  majority  of  the  cases.  At  autopsy  has  been  found  deep 
pigmentation  of  the  liver  and  pancreas,  associated  with 
cirrhosis,  and  in  cases  carefully  examined  macroscopi- 
cally  and  histologically  interstitial  pancreatitis.  An 
ochre-colored  pigment  giving  the  microchemical  reac- 
tions of  iron  is  present  in  the  parenchymatous  cells  of 
the  liver,  pancreas,  and  other  glands,  in  the  muscle- 
fibres  of  the  heart,  in  the  interstitial  tissue  of  these 
organs,  and  in  the  lymphatic  glands. 

Facts  relating  to  the  incidence  of  the  disease  are  of 
interest.  Only  one  recorded  instance  of  haemochro- 
matosis  (the  case  of  Abbott),  or  of  bronzed  diabetes,  has 
occurred  in  the  female.  The  age  of  the  individuals 
affected  with  bronzed  diabetes  has  varied  between 
thirty-three  and  sixty-two  years,  the  greatest  number 
occurring  in  the  fourth  and  fifth  decades.  The  cases  of 
simple  hsemochromatosis  fall  within  these  limits.  It  has 
been  believed  that  the  disease  is  more  common  in 
France  than  elsewhere,  and  this  is,  to  a  certain  extent, 
indicated  by  the  fact  that  of  twenty-four  cases  seven- 


292  DISEASE    OF   THE    PANCREAS. 

teen  have  been  observed  in  that  country.  Simple 
hsemochromatosis,  however,  has  been  described  more 
frequently  by  German  writers. 

The  pathogenesis  of  the  condition  has  been  the  sub- 
ject of  varied  speculation.  Hanot  and  Chauffard,  and 
subsequently  Hanot  and  Schachmann,  have  maintained 
that  the  primary  etiological  factor  is  diabetes  mellitus, 
that  the  diabetic  alteration  of  the  blood,  in  conjunction 
with  endarteritis,  which  they  have  found  constant  in 
their  cases,  causes  a  disturbance  of  the  nutrition  of  the 
liver  cells,  an  alteration  of  pigment  metabolism,  and 
a  deposition  of  pigment  within  the  hepatic  cells.  The 
excess  of  pigment  so  formed  is  reabsorbed  by  the  capil- 
laries and  diffused  possibly  in  the  form  of  emboli  over 
the  entire  organism. 

Letulle,  finding  the  same  process  of  pigment  deposi- 
tion in  other  organs — for  example,  in  the  heart — 
that  takes  place  in  the  liver,  comes  to  the  conclusion 
that  the  pigment  is  formed  in  the  cells  in  which  it  is 
found  from  the  haemoglobin  of  the  blood.  He  regards 
diabetes  as  primary,  and  thinks  that  disintegration  of 
haemoglobin  occurs  under  the  influence  of  hypergly- 
caemia.  Braultand  Galliard,  Hernandez,  Mosse,  Rendu, 
De  Massary,  and  Potier  also  give  prominence  to  dia- 
betes as  the  important  factor  in  producing  pigmenta- 
tion. 

A  second  smaller  group  of  writers  thinks  that  the  pig- 
mentation  is   produced  by  a   primary  disease   of    the 


H.^MOCHROMATOSIS   AND    BRONZED    DIABETES.      293 

blood,  that  as  a  result  of  some  fundamental  cause  there 
is  an  alteration  of  the  blood  and  subsequent  formation 
of  pigment  from  altered  haemoglobin.  The  relation 
of  the  concomitant  diabetes  and  cirrhosis  then  remain 
to  be  explained.  Buss,  in  accordance  with  an  obsolete 
theory  of  diabetic  metabolism,  suggests  that  glycsemia 
may  be  the  result  of  incomplete  oxidation  of  oxidizable 
carbon,  resulting  in  turn  from  a  diminished  oxygen- 
carrying  power  of  the  altered  haemoglobin. 

P.  Marie  thinks  that  there  follows  the  action  of  some 
primitive  cause  a  dissolution  of  the  haemoglobin,  which 
is  transformed  by  various  cells  of  the  body  into  pig- 
ment and  is  deposited  in  these  cells.  The  pigment 
in  turn  causes  degeneration  and  destruction  of  the 
cells  in  which  it  accumulates,  and  consequently  chronic 
interstitial  inflammation  of  various  organs,  notably 
the  liver.  Bronzed  diabetes  is  neither  clinically  nor 
pathologically  classic  diabetes,  but  is  a  distinct  mor- 
bid entity,  as  is,  according  to  his  belief,  pancreatic 
diabetes  ;  and  if,  he  says,  it  should  be  necessary  to  com- 
pare the  condition  with  any  other,  he  would  turn  his 
attention  to  pancreatic  diabetes.  Acard,  Dutourier, 
and  Jeanselme  reiterate  the  conception  of  Marie,  and 
suggest  that  diabetes  perhaps  is  only  an  accessory 
phenomenon  which  appear^  with  a  certain  degree  of 
chronic  interstitial  pancreatitis.  Anschiitz  has  convinced 
himself  that  the  associated  diabetes  finds  its  cause  in 
chronic  interstitial  pancreatitis,  which  like   the  accom- 


294  DISEASE    OF   THE    PANCREAS. 

panying  cirrhosis  of  the  liver  is,  he  believes,  a  manifes- 
tation of  some  .underlying  condition. 

French  writers  who  have  described  cases  of  "  dia- 
bete  bronze"  do  not  identify  the  disease  with  the 
haemochromatosis  of  von  Recklinghausen.  In  the  very 
early  cases  no  examination  of  the  chemical  nature  of 
the  pigment  was  made.  Hernandez  demonstrated  that 
the  brownish-yellow  granules  found  by  him  in  the 
epithelial  cells  of  the  liver,  pancreas,  and  kidney,  in  the 
muscle-cells  of  the  heart,  in  the  connective  tissue  of 
these  organs,  and  in  the  lymphatic  glands  gave  the 
microchemical  reactions  known  to  be  characteristic  of 
iron.  In  the  case  of  Hernandez  and  in  subsequent  cases 
this  yellowish-brown  pigment  agrees  in  morphology  and 
in  location  with  the  haemosiderin  of  von  Recklinghausen. 

Buss  reported  a  case  of  diabetes  associated  with  cir- 
rhosis of  the  liver  and  chronic  pancreatitis  with  general 
haemochromatosis.  He  finds  not  only  the  iron-contain- 
ing but  the  iron-free  pigment  in  locations  correspond- 
ing to  those  mentioned  by  von  Recklinghausen.  On 
the  one  hand  there  is  no  reason  to  doubt  that  the  pig- 
mentation in  this  case  is  identical  with  that  of  haemo- 
chromatosis, and  on  the  other  hand  the  case  presents 
the  clinical  and  pathological  picture  to  which  Hanot  has 
given  the  name  "diabete  bronze." 

The  case  described  in  the  present  chapter  holds  a 
position  intermediate  between  simple  haemochromatosis 
and    the   bronzed    diabetes.      Associated   with    haemo- 


H.^MOCHROMATOSIS    AND    BRONZED    DIABETES.      295 

chromatosis  there  is  bronzing  of  the  skin,  cirrhosis 
of  advanced  grade,  and  chronic  interstitial  pancrea- 
titis. Diabetes  was,  however,  not  present.  It  is  evi- 
dent that  the  generalized  pigmentation  of  bronzed  dia- 
betes is  the  haemochromatosis  of  von  Recklinghausen. 

Etiology  of  Hcemochromatosis.  —  When  considering 
what  etiological  factors  are  concerned  in  the  deposition  of 
great  quantities  of  pigment  in  the  liver  and  other  organs, 
we  direct  our  attention  to  the  blood,  since  it  cannot  be 
doubted  that  this  iron-containing  material  is  derived 
more  or  less  directly  from  the  haemoglobin.  It  is  well 
known  that  in  pernicious  anaemia  with  active  blood  de- 
struction there  is  a  deposition  of  iron  within  the  liver 
and  other  organs,  but  pigmentation  of  the  character 
under  consideration  is,  at  least  in  the  great  majority  of 
cases,  not  found.  A  considerable  proportion  of  the 
cases,  both  of  simple  haemochromatosis  and  of  haemo- 
chromatosis associated  with  diabetes,  have  been  accom- 
panied by  conditions  which  involve  active  destruction 
of  the  red  blood-corpuscles.  Hindenlang's  case  of  gen- 
eral pigmentation,  almost  certainly  one  of  haemochro- 
matosis, was  associated  with  morbus  maculosus  Werl- 
hofii.  In  four  other  cases  purpuric  eruptions  have  been 
observed.  In  several  there  have  been  local  hemorrhagic 
conditions  ;  in  the  case  of  Buss,  for  example,  there  was 
found  at  autopsy  hemorrhagic  pleurisy  and  peritonitis 
and  hemorrhagic  pachymeningitis.  Other  forms  of  local 
hemorrhage  have  been  noted. 


296  DISEASE   OF    THE   PANCREAS. 

The  haemorrhagic  lesions  cited  present  considerable 
variety,  and  in  many  cases  have  been  late  manifesta- 
tions of  the  disease.  Moreover,  local  hemorrhages 
have  not  always  been  demonstrable.  It  is,  then, 
unnecessary  to  assume  that  the  haemoglobin  from 
which  is  formed  the  pigment  arises  from  the  destruc- 
tion of  red  corpuscles  of  extravasated  blood.  It  seems 
probable  that  with  some  primitive  alteration  of  the 
blood  there  is  a  tendency  to  local  hemorrhage  ;  the 
hemorrhage  is  merely  a  manifestation  of  the,  as  yet 
obscure,  disease  of  the  blood  which,  associated  with  in- 
travascular destruction  of  red  corpuscles,  causes  pig- 
ment deposition. 

In  a  case  of  Jeanselme  examination  of  the  blood 
demonstrated  the  presence  of  a  moderate  grade  of 
anaemia,  but  otherwise  no  marked  change  was  noted. 
Coaofulation  was  not  retarded. 

Attempts  have  been  made  to  reproduce  experiment- 
ally the  pigmentation  found  in  human  beings.  Two 
methods  have  been  employed:  (i)  Conditions  resem- 
bling those  of  local  hemorrhage  are  reproduced,  for  ex- 
ample, by  injecting  blood  into  the  peritoneum.  (2) 
Haemoglobin  is  set  free  within  the  circulating  blood  by 
the  use  of  toxic  substances  which  cause  destruction  of 
the  red  blood-corpuscles.  Auscher  and  Lapicque  and 
Meunier  have  attempted  by  these  means  to  produce 
the  general  pigmentation  of  the  organs  found  in 
bronzed  diabetes.     Auscher  and  Lapicque,  by  injecting 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      297 

blood  into  the  peritoneum,  caused  accumulation  of  an 
iron-containing  pigment  in  considerable  quantity  in  the 
spleen,  but  in  very  small  quantity  in  the  liver.  In  cases 
of  hsemochromatosis,  however,  the  liver  is  the  promi- 
nent seat  of  pigment  accumulation. 

It  has  long  been  known  that  toluylendiamin  causes 
a  destruction  of  the  red  blood-corpuscles,  large  doses 
producing  in  dogs  haemoglobinuria.  By  the  use  of 
this  substance  numerous  experimenters  have  caused 
the  deposition  of  an  iron-containing  pigment  in  the  liver 
and  other  organs.  Meunier,  attempting  to  reproduce 
in  dogs  the  pigmentation  of  bronzed  diabetes,  succeeded 
by  the  repeated  injection  of  small  doses  in  obtaining 
an  iron-containing  pigment  in  moderate  amount  in  the 
liver,  lymphatic  glands,  spleen,  and  bone-marrow.  The 
immense  iron  accumulation  of  haemochromatosis,  how- 
ever, has  not  been  reproduced,  so  that  experiments 
have  thrown  but  little  light  upon  the  pathogenesis  of 
the  condition. 

As  already  indicated,  many  of  those  who  have  studied 
cases  of  bronzed  diabetes  regard  diabetes  as  the  essen- 
tial etiological  factor.  Upon  an  insufficient  basis  active 
blood  destruction  has  been  assumed  to  be  a  result  of 
the  diabetic  condition.  In  the  ordinary  form  of  diabetes, 
however,  no  accumulation  of  iron  takes  place  in  the 
liver  or  other  organs,  as  has  been  shown  in  cases 
studied  by  Zaleski  and   by  Kretz.     There  is,   on  the 


298  DISEASE   OF   THE   PANCREAS. 

contrary,  reason  to  believe  that  diabetes  is  secondary 
to  haemochromatosis. 

Relation  of  HcE7nochi^omatosis  to  Chro7iic  Interstitial 
Inflammatio7i. — In  cases  of  bronzed  diabetes  two  promi- 
nent features  in  addition  to  generalized  pigmentation 
are  diabetes  and  cirrhosis  of  the  liver,  and  it  is  to  the 
second  factor  that  a  number  of  writers  have  directed 
their  attention  in  attempting  to  explain  the  pigmentation. 
It  is  to  be  recalled,  moreover,  that  cirrhosis  of  the  liver 
has  been  present  in  cases  of  simple  haemochromatosis. 
In  all  instances  of  haemochromatosis,  both  with  and  with- 
out diabetes,  the  greatest  pigment  accumulation  has  been 
in  the  liver,  and  consequently  a  disturbed  chromogenic 
function  of  that  organ  has  suggested  itself  Is  the 
altered  metabolism  accompanying  cirrhosis  of  the  liver 
to  be  regarded  as  the  essential  etiological  factor  ? 

A  study  of  the  process  of  pigment  accumulation  in 
widely  separated  organs  throws  light  upon  the  seat  of 
its  formation.  The  glands  I  have  studied  most  care- 
fully are  the  liver,  the  pancreas,  and  the  adrenal 
glands.  When  pigment  is  in  moderate  quantity,  it 
is  present  as  relatively  fine  round  granules  occupying 
that  part  of  the  cell  most  distant  from  the  capillaries, — 
that  is,  in  acinous  glands,  the  part  next  the  lumen. 
With  greater  accumulation  the  whole  cell-body  contains 
pigment  granules,  and  finally  almost  the  entire  proto- 
plasm is  replaced  by  them.  Changes  at  the  same  time 
may  be  observed  in  the  nucleus  of  the  cell.     It  becomes 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      299 

smaller,  its  outline  often  becomes  irregular,  and  it  as- 
sumes a  shrivelled  appearance.  In  cells  which  at  first 
sight  appear  to  be  mere  masses  of  granules  and  glob- 
ules of  pigment,  with  careful  focusing  a  very  faintly- 
staining  vesicular  nucleus  is  occasionally  seen,  while 
more  frequently  are  found  pigment  masses  without  any 
trace  of  nucleus,  but  still  maintaining  the  cell  outline. 
Finally,  the  cell  outline  is  lost  and  a  clump  of  pigment 
particles  of  very  variable  size  lies  free  in  the  tissue. 

The  same  process  observed  in  the  liver  takes  place 
in  the  pancreas  and  adrenal  gland,  in  the  muscle-cells 
of  the  heart,  and  in  many  other  tissues.  It  is  therefore 
improbable  that  the  pigment  is  transported  as  emboli 
or  in  phagocytic  cells  from  the  liver.  Much  more 
probable  is  it  that  the  same  process  is  taking  place 
simultaneously  in  all  the  organs  concerned,  that  the 
pigment  is  elaborated  by  the  cells  in  which  it  is  found 
from  iron-containinof  material  derived  from  haemoglobin 
and  dissolved  in  the  surrounding  lymph. 

Doubtless  for  the  production  of  hsemochromatosis 
some  factor  is  necessary  besides  the  mere  disintegration 
of  red  corpuscles  and  the  setting  free  of  haemoglobin. 
Its  absence  in  many  conditions  associated  with  blood 
destruction  sufficiently  proves  this  point.  Of  a  series 
of  cases  of  cirrhosis  of  the  liver  studied  by  Kretz, 
in  about  one-half  was  found  an  accumulation  of 
an  iron-containing  pigment  resembling  haemosiderin. 
He   comes  to  the   conclusion  that  some  toxic  matter 


300  DISEASE    OF   THE   PANCREAS. 

circulating  in  the  blood  causes  degeneration  of  the 
liver-cells,  and  at  the  same  time  acts  injuriously 
upon  the  red  corpuscles.  It  is  the  association  of  the 
two  conditions  which  simultaneously  produces  cirrhosis 
and  pigmentation.  In  haemochromatosis  the  toxic  ma- 
terial causing  blood  destruction  may  be  of  such  a  nature 
that  it  acts  injuriously  upon  the  cells  of  the  liver  and 
other  organs,  so  that  they  transform  into  insoluble  hsemo- 
siderin  the  soluble  blood  pigment  which  reaches  them. 
Alcohol  may  possibly  under  certain  conditions  have  this 
action.  Such  speculations  merely  indicate  the  complex- 
ity of  the  conditions  which  underlie  this  generalized 
pigmentation. 

Degenerate  parenchymatous  cells  overloaded  with 
pigment  are,  in  the  case  which  I  have  studied,  very  abun- 
dant, and  can  be  readily  demonstrated  without  prolonged 
search.  We  have  thus  an  efficient  factor  for  the  produc- 
tion of  chronic  interstitial  inflammation  ;  fibrous  stroma 
replaces  the  cells  which  are  destroyed.  In  the  liver 
newly-formed  fibrous  tissue  invades  the  lobule  along 
the  central  vein,  and  in  places  sends  out  fine 
radiating  bands  along  the  capillaries  between  the 
columns  of  the  liver-cells.  The  fibrous  tissue  about 
the  central  vein  and  between  the  lobules  contains 
large  quantities  of  pigment,  which  is  for  the  most 
part  extracellular,  since  the  cells  in  which  it  was  formed 
have  undergone  degeneration.  When  it  is  massed  in 
large  quantity,  there  is  usually  evidence  of  active  cell 


HEMOCHROMATOSIS   AND   BRONZED    DIABETES.      301 

proliferation.  In  general  the  interlobular  tissue  is 
poor  in  cells,  but  in  such  areas  proliferation  is  indi- 
cated by  the  presence  of  small  round  cells.  Two 
factors  are,  I  believe,  active  in  producing  the  sclerosis  : 
(i)  Pigmentary  degeneration  of  the  parenchymatous 
cells  ;  (2)  irritation  produced  by  the  presence  of  the 
pigment  in  the  interstitial  tissue. 

Relation  of  HcBmochroniatosis  to  Diabetes. — In  the 
case  I  have  described  the  pancreas  next  to  the  liver 
is  the  organ  most  conspicuously  pigmented.  Extreme 
pigmentation  and  consequent  degeneration  of  paren- 
chymatous cells  has  occurred,  and  the  organ  is  the  seat 
of  chronic  interstitial  inflammation  of  the  interacinar 
type. 

The  pancreas  has  been  superficially  examined  in 
many  of  the  reported  cases  of  bronzed  diabetes,  but 
in  those  accompanied  by  a  record  of  its  microscopic 
appearance  chronic  interstitial  pancreatitis  has  been 
described.  The  absence  of  atrophy  has  doubtless  in 
some  instances  prevented  the  recognition  of  inter- 
stitial inflammation.  In  but  two  cases  has  the  gland 
been  found  smaller  than  normal,  while  it  is  frequently 
described  as  voluminous,  enlarg-ed,  or  normal  in  size. 
In  seven  cases  the  weight  is  recorded.  The  mean  of 
the  figures  given,  varying  between  ninety-five  and  one 
hundred  and  ninety-five  grammes,  is  125.7  grammes, — 
about  one-half  greater  than  the  normal  weight  of  the 
organ.      The  average  weight  of  the  liver  recorded  in 


302  DISEASE    OF   THE    PANCREAS. 

thirteen  cases  of  bronzed  diabetes  is  two  thousand 
four  hundred  and  ninety-seven  grammes.  Both  cir- 
rhosis and  chronic  pancreatitis  are  associated  with 
hypertrophy. 

As  far  as  one  is  able  to  determine  from  recorded 
cases,  chronic  interstitial  pancreatitis  is  constantly  asso- 
ciated with  bronzed  diabetes.  In  the  present  case  of 
hsemochromatosis  without  diabetes  the  pancreas  weighs 
one  hundred  and  seventy  grammes,  almost  twice  the 
normal  weight,  and  is  the  seat  of  interstitial  inflamma- 
tion of  moderate  intensity.  The  lesion  affects  primarily 
the  parenchymatous  cells,  and  the  newly-formed  fibrous 
tissue,  diffusely  distributed,  bears  no  constant  relation 
to  the  lobules.  The  alterations  of  the  islands  of 
Langerhans  are  as  follows :  Pigment  is  abundant  in 
the  cells,  and  tends  to  accumulate  in  that  part  which 
is  most  distant  from  the  capillaries.  The  island  is 
usually  embedded  in  a  capsule-like  mass  of  fibrous 
tissue  containing  pigment  granules,  and  strands  of 
similar  tissue  often  penetrate  the  island,  following  its 
capillaries. 

Pancreatitis  present  is  of  the  interacinar  type,  and, 
tending  to  invade  the  islands  of  Langerhans,  is  that 
which  is  most  frequently  accompanied  by  diabetes. 
In  the  present  instance  the  lesion  is  little  advanced, 
and  has  caused  such  incomplete  destruction  of  the 
islands  of  Langerhans  that  diabetes  has  not  ensued. 
The    individual    had    been    in    good    health  until     at- 


tacked  by  typhoid  fever.  When,  as  in  this  case, 
haemochromatosis  without  diabetes  has  been  observed 
at  autopsy,  death  has  been  due  to  some  intercur- 
rent affection  having  no  apparent  relation  to  the 
antecedent  disease.  The  fatal  illness  in  most  in- 
stances begins  with  symptoms  of  diabetes.  In  the 
present  instance  typhoid  fever  caused  death  of  the 
individual  before  chronic  interstitial  pancreatitis  had 
reached  a  sufficient  grade  of  intensity  to  produce 
glycosuria.  Thus  haemochromatosis  was  prevented 
from  reaching  its  usual  termination — diabetes. 

Haemochromatosis,  a  distinct  morbid  entity,  is  charac- 
terized by  wide-spread  deposition  of  pigment  in  various 
tissues  of  the  body.  It  is  associated  with  chronic  inter- 
stitial inflammation,  notably  of  the  liver  and  pancreas. 
Parenchymatous  cells  undergo  pigmentation  and  degen- 
eration, and  fibrous  stroma  fills  the  defect  thus  produced. 
In  the  pancreas  chronic  inflammation  is  of  the  interacinar 
type,  and  the  islands  of  Langerhans  are  implicated  in 
the  lesion.  When  interacinar  pancreatitis  has  reached 
a  certain  grade  of  intensity,  diabetes  mellitus  ensues, 
and  is  usually  the  terminal  event  in  cases  of  haemo- 
chromatosis. 


CHAPTER    XIII. 

THE    SYMPTOMS    AND    TREATMENT  OF    PANCREATIC   DISEASE. 

In  the  present  chapter  the  attempt  will  be  made  to 
review  the  facts  previously  considered  and  to  point 
out  their  relation  to  diagnosis  and  treatment.  Disease 
of  the  pancreas  is  rarely  recognized  during  life,  since 
the  symptoms,  though  not  infrequently  of  great  sever- 
ity, present  little  that  is  characteristic  upon  superficial 
examination.  The  physiology  of  the  organ  being  well 
understood,  it  may  seem  at  first  sight  surprising  that 
disturbances  of  function  are  not  more  evident,  but  a 
variety  of  causes  tends  to  obscure  the  manifestations 
of  pancreatic  disease. 

Situated  behind  the  stomach,  almost  in  contact  with 
the  vertebral  column,  the  organ  is  not  palpable  in 
health,  and  alterations  of  size  comparable  to  those 
readily  recognized  in  the  liver  are  not  discernible. 

Destructive  lesions,  such  as  suppuration,  hemor- 
rhagic necrosis,  and  chronic  inflammation,  or  the  pres- 
ence of  cysts  or  new  growth,  may  so  impair  the  func- 
tional activity  of  the  gland  that  on  the  one  hand  it  no 
longer  furnishes  the  normal  supply  of  digestive  fer- 
ments, while  on  the  other  hand  it  may  become 
incapable  of  exerting  its  normal  influence  upon  carbo- 
hydrate metabolism.  Alteration  of  the  so-called  ex- 
304 


SYMPTOMS  AND  TREATMENT.        305 

ternal  secretion  is  indicated  by  disturbance  of  digestion, 
while  alteration  of  the  internal  function  finds  its  expres- 
sion in  glycosuria. 

The  independence  of  the  two  important  functions  of 
the  gland  has  received  sufficient  demonstration  in  the 
preceding  pages.  The  secreting  alevoli  elaborate  the 
pancreatic  ferments,  while  the  islands  of  Langerhans, 
having  no  communication  with  the  pancreatic  ducts, 
control  the  assimilation  of  sugars.  Obstruction  of  the 
ducts  preventing  the  entrance  of  the  pancreatic  juice 
into  the  duodenum  causes  partial  destruction  of  the 
parenchyma.  The  chronic  interstitial  inflammation 
which  results  is  of  the  interlobular  type,  and  the  islands 
of  Langerhans  are  implicated  only  when  the  lesion  is 
far  advanced.  In  such  case,  althoupfh  characteristic  dis- 
turbances  of  digestion  may  suggest  the  presence  of  a 
pancreatic  lesion,  carbohydrate  metabolism  is  undis- 
turbed and  glycosuria  is  absent.  The  islands  of  Lan- 
gerhans, on  the  contrary,  may  be  so  altered  by  the 
hyaline  change  previously  described  in  detail  that  dia- 
betes results,  though  the  secreting  parenchyma  is  little, 
if  at  all,  affected. 

The  recognition  of  pancreatic  disease  is  further 
obscured  by  the  fact  that  lesions  affecting  only  a  part 
of  the  gland  may  be  unaccompanied  by  symptoms. 
Experimental  extirpation  of  the  pancreas  is  followed 
not  only  by  glycosuria,  but  by  characteristic  changes 
in  the  digestion  and  absorption  of  proteids  and   fats. 


3o6  DISEASE    OF   THE   PANCREAS. 

Partial  extirpation  of  the  gland  is  followed  by  diabetes 
only  when  the  part  remaining  is  a  very  small  fraction 
of  the  whole,  and  experiments  have  shown,  moreover, 
that  a  relatively  small  part  of  the  gland  is  capable  of 
effecting  intestinal  digestion.  Even  complete  occlusion 
of  the  larger  duct  is  not  wholly  uncompensated,  since 
the  smaller  duct  of  Santorini  anastomosing  with  the 
larger  may  in  a  considerable  proportion  of  all  indi- 
viduals afford  an  outlet  for  the  pancreatic  secretion. 

The  difficulty  of  diagnosis  is  increased  by  the  fact 
that  disease  of  the  organ  is  seldom  uncomplicated,  but 
is  usually  consequent  upon  changes  in  the  duodenum, 
liver,  or  bile  passages.  Gall-stones  lodged  in  the  com- 
mon bile  duct,  for  example,  are  a  frequent  cause  of 
both  acute  and  chronic  inflammation  of  the  gland.  A 
recognition  of  such  relationship  indeed  may  be  an 
important  aid  to  the  diagnosis  of  obscure  pancreatic 
affections. 

Symptoms  of  Pancreatic  Disease. — Certain  symptoms, 
notably  pain  and  tumor,  by  their  localization  may  indi- 
cate that  the  organ  is  the  seat  of  disease.  Pain  in  the 
epigastrium  is  an  inconstant  symptom  of  pancreatic 
affections,  and  may  be  absent  even  when  the  gland  is 
occupied  by  an  abscess  or  by  carcinoma.  Intermittent 
pain  resembling  that  of  biliary  colic  has  been  observed 
in  association  with  obstruction  of  the  pancreatic  duct 
due  to  calculi  or  other  cause. 

Under  normal  conditions  the  pancreas  is  not  palpa- 


SYMPTOMS  AND  TREATMENT.        307 

ble,  but  in  individuals  with  thin  abdominal  walls,  accord- 
ing to  Osier,  particularly  in  women  with  enteroptosis, 
the  orean  can  be  felt.  Acute  or  chronic  inflammation 
rarely,  if  ever,  causes  a  recognizable  enlargement  of 
the  gland.  A  deep-seated  epigastric  tumor  in  associa- 
tion with  acute  suppurative  or  gangrenous  pancreatitis  is 
referable  to  a  peripancreatic  abscess  limited  to  the  lesser 
peritoneal  cavity.  Such  a  mass  overlying  the  pancreas 
is  situated  behind  the  stomach  and  colon,  is  movable, 
and  does  not  descend  with  respiration.  A  cyst  or  new 
growth  occupying  the  gland  may  form  a  palpable  mass 
in  the  same  region. 

It  is  desirable  to  consider :  first,  the  symptoms  which 
result  from  impairment  of  the  internal  function  of  the 
pancreas  ;  second,  symptoms  which  follow  alterations 
of  the  external  secretion. 

Diabetes  and  Alimentary  Glycosuria. — Experimental 
studies  conducted  upon  a  large  variety  of  animal 
species  have  conclusively  shown  that  complete  extirpa- 
tion of  the  pancreas  is  followed  by  a  condition  iden- 
tical with  diabetes  mellitus  of  man.  The  numerous 
clinical  observations  previously  cited  have  shown  that 
diabetes  is  associated  with  destructive  lesions  of  the 
gland  in  considerably  more  than  one-half  of  all  cases. 
Since  the  islands  of  Langerhans  are  the  effective  agents 
in  the  regulation  of  carbohydrate  metabolism,  only 
those  lesions  which  affect  these  structures  cause  the 
disease.     When,   for  example,   the    interacinar   islands 


3o8  DISEASE    OF  THE    PANCREx\S. 

alone  are  destroyed  by  hyaline  degeneration,  glycosuria 
and  other  manifestations  of  diabetes  mellitus  are  sec- 
ondary to  the  lesion.  Hence,  permanent  glycosuria 
may  follow  a  lesion  which,  leavdng  unaffected  the  secret- 
ing parenchyma,  is  unaccompanied  by  any  disturbance 
of  pancreatic  digestion. 

Diabetes,  however,  may  exist  in  the  absence  of  any 
demonstrable  lesion  of  the  pancreas  ;  doubtless  the  in- 
fluence of  the  islands  of  Langerhans  is  only  one  of  the 
factors  which  regulate  the  assimilation  of  sugars,  and 
diabetes  may  be  the  result  of  changes  other  than  those 
which  affect  the  pancreas.  Hence,  permanent  glyco- 
suria does  not  give  conclusive  proof  that  a  lesion  of  the 
interacinar  islands  exists  ;  but  in  considerably  more  than 
fifty  per  cent,  of  cases  such  a  lesion  is  present.  On 
the  other  hand,  where  a  lesion  of  the  pancreas  does  not 
implicate  the  islands  of  Langerhans,  diabetes  is  absent, 
and  hence  it  results  that  by  far  the  greater  number  of 
pancreatic  lesions  are  unaccompanied  by  the  disease. 

The  attempt  has  been  unsuccessfully  made  to  define 
certain  clinical  symptoms  characteristic  of  diabetes,  when 
due  to  lesions  of  the  pancreas.  Lancereaux,  notably, 
has  described  a  special  type  of  diabetes  referable  to  pan- 
creatic disease  and  characterized  by  extreme  emacia- 
tion, in  company  with  intense  thirst,  voracious  appetite, 
and  abundant  polyuria.  He  designates  the  condition 
*'  diabete  maigre,"  and  distinguishes  it  from  diabetes  with 
obesity,  "diabete  gras,"  unaccompanied  by  pancreatic 


SYMPTOMS  AND  TREATMENT.        309 

disease.  His  views  have  received  some  acceptance,  but 
few  clinicians  maintain  that  it  is  possible  to  recognize 
the  sharp  distinction  claimed  by  him.  Many  writers, 
Lepine,  Hansemann,  Williamson,  among  others,  have 
on  the  one  hand  cited  cases  in  which  emaciation  was 
absent,  though  diabetes  accompanied  pancreatic  dis- 
ease ;  while  on  the  other  hand  in  patients  suffering 
with  diabetes  and  emaciation  they  have  discovered  no 
alteration  of  the  pancreas.  Removal  of  the  gland  in 
animals  is  followed  by  diabetes  with  rapid  emaciation, 
absence  of  pancreatic  secretion  being  followed  by  grave 
disturbances  of  digestion  and  absorption.  In  human 
cases,  however,  diabetes  may  be  caused  by  lesions  of 
the  gland  which  destroy  the  islands  of  Langerhans,  yet 
leave  almost  intact  the  secreting  parenchyma. 

Wide-spread  lesions  of  the  organ,  destroying  both 
secreting  acini  and  interacin'ar  islands  are  accompanied 
by  diabetes  only  when  very  little  of  the  gland  remains. 
After  partial  extirpation  in  dogs,  diabetes  does  not 
result  if  more  than  an  eighth  to  a  twelfth  be  spared. 
For  a  similar  reason  glycosuria  is  rarely  a  symptom  of 
acute  hemorrhagic  and  gangrenous  pancreatitis,  which 
usually  leaves  relatively  unimpaired  a  considerable  part 
of  the  organ.  Diffuse  carcinoma  attacking  the  pan- 
creas may  also  destroy  both  islands  of  Langerhans  and 
secreting  parenchyma.  Here,  too,  only  when  the  lesion 
has  almost  wholly  replaced  the  gland  may  glycosuria 
and  other  symptoms  of  diabetes  be  expected. 


3IO  DISEASE    OF   THE   PANCREAS. 

Minkowski  has  shown  that  alimentary  glycosu7'ia  not 
infrequently  follows  partial  removal  of  the  pancreas 
when  a  considerable  part  still  remains.  Diabetes  does 
not  result,  but  the  ability  of  the  organ  to  exert  its 
normal  influence  on  carbohydrate  metabolism  is  im- 
paired, and  if  sugar  is  given  to  the  animal  in  large 
amount  temporary  glycosuria  results.  Wille  has  re- 
cently observed  alimentary  glycosuria  in  association 
with  lesions  of  the  pancreas,  and  thinks  that  this  symp- 
tom may  be  regarded  as  an  index  to  the  presence  of 
pancreatic  disease.  The  ability  to  assimilate  sugar  was 
tested  in  eight  hundred  patients  suffering  with  a  great 
variety  of  diseases.  In  the  morning,  before  other  food 
had  been  taken,  were  administered  from  seventy  to  one 
hundred  grammes  of  grape  sugar  dissolved  in  a  half- 
litre  of  tea  or  coffee.  The  urine  was  voided  just  before 
the  sugar  was  taken  and  was  then  tested  at  intervals  of 
two  hours  ;  when  the  test  was  positive,  sugar  usually 
appeared  at  the  end  of  two  hours. 

Of  eight  hundred  individuals  upon  whom  this  test 
was  made,  seventy-seven  subsequently  died  and  au- 
topsies were  performed.  Alimentary  glycosuria  had 
been  found  in  fifteen  of  those  who  came  to  autopsy,  and 
in  ten  of  these  were  present  grave  lesions  of  the  pan- 
creas, chronic  interstitial  inflammation,  or  carcinoma  of 
the  gland,  either  primary  or  secondary  to  tumors  in  the 
stomach,  liver,  or  gall-bladder.  Although  alimentary 
glycosuria    may  occur  in    the    absence    of   pancreatic 


SYMPTOMS  AND  TREATMENT.        311 

disease  and  is  doubtless  frequently  associated  with  a 
variety  of  conditions,  notably  hysteria  and  other  neu- 
roses, chronic  alcoholism,  exophthalmic  goitre,  etc.,  its 
presence,  according  to  Wille,  suggests  the  existence  of 
a  lesion  of  the  pancreas  and  has  considerable  value  for 
diagnosis. 

Disturba7ices  of  Digestion. — Symptoms  which  follow 
impairment  of  the  digestive  or  external  function  of  the 
pancreas  have  not  been  very  clearly  defined,  and, 
though  certain  facts  have  been  established,  clinical 
observations  are  often  divergent.  The  pancreatic 
juice,  it  is  well  known,  contains  ferments  which  aid  in 
the  digestion  of  proteids,  fats,  and  carbohydrates,  yet 
it  is  not  the  only  secretion  concerned  in  the  digestion 
of  any  one  of  these  substances.  Impaired  assimilation 
of  proteids  and  fats  is  more  readily  recognized  than 
alterations  affecting  the  digestion  of  carbohydrates, 
and  hence  has  been  assigned  greater  diagnostic 
significance. 

Claude  Bernard  destroyed  the  pancreas  of  dogs  by 
injecting  oil  or  other  bland  substance  into  the  larger 
duct,  and  observed  that  the  faeces  contained  in  abun- 
dance food  material  which  had  undergone  little  change, 
— for  example,  undigested  muscle-fibres  or  even  large 
pieces  of  meat,  together  with  fat,  at  times  in  such  quan- 
tity that  when  cold  it  congealed  as  a  layer  covering  the 
surface  of  the  faecal  mass.  Subsequent  observers  have 
studied  by  somewhat  more  accurate  methods   the  dis- 


312  DISEASE    OF   THE    PANCREAS. 

turbances  which  Claude  Bernard  described.  Abelmann 
found  after  removing  the  pancreas  in  dogs  that  all  fat 
taken  with  the  food  reappeared  in  the  faeces  ;  an  excep- 
tion was  the  emulsified  fat  of  milk,  of  which  about  fifty- 
three  per  cent,  disappeared.  Under  normal  conditions 
little  more  than  five  per  cent,  of  fat  escapes  absorption. 
Hedon  and  Ville  claim  that  the  statement  of  Abelmann 
is  somewhat  exaggerated  ;  they  found  that  eighteen  per 
cent,  of  fat  which  was  not  emulsified  might  undergo 
absorption  when  the  gland  was  completely  removed. 
After  partial  extirpation,  even  when  so  performed  that 
the  pancreatic  juice  no  longer  reaches  the  intestine,  at 
least  half  the  fat  ingested  is,  they  claim,  absorbed. 
After  complete  removal  of  the  organ,  according  to 
Abelmann,  fat  is  still  split,  and  about  four-fifths  of  that 
which  is  unused  is  represented  in  the  faeces  by  fatty 
acids. 

In  the  experiments  of  Abelmann  after  total  excision 
of  the  pancreas  only  about  forty-four  per  cent,  of  the  pro- 
teids  ingested  was  absorbed,  while  after  partial  removal 
fifty-four  per  cent,  was  retained.  Under  normal  condi- 
tions not  more  than  one  or  two  per  cent,  of  nitrogenous 
material  is  unabsorbed.  Loss  of  the  pancreas  also  alters 
the  normal  digestion  of  carbohydrates,  and,  according 
to  Abelmann,  twenty  to  forty  per  cent,  of  starch  may 
reappear  in  the  faeces,  having  undergone  no  transform- 
ation into  sugar.  Subsequent  experimenters  have  con- 
firmed the  observations  of  Abelmann. 


SYMPTO.MS    AND    TREATMENT.  313 

Disturbances  of  digestion  similar  to  those  which  fol- 
low experimental  extirpation  of  the  gland  have  been 
noted  in  human  cases  where  the  pancreas  has  been 
partially  destroyed  by  chronic  inflammation,  by  cysts, 
or  by  new  growths  ;  occlusion  of  the  duct  by  calculi  or 
by  tumor  may  have  the  same  effect.  Even  where  the 
gland  is  injured  or  its  larger  duct  obstructed  pancreatic 
juice  in  considerable  amount  may  still  reach  the  intes- 
tine, and  in  many  cases  digestion  proceeds  with  no 
manifest  impairment. 

In  human  cases  disturbance  of  proteid  digestion  may 
be  recognizable  by  the  presence  of  unaltered  muscle- 
fibres  in  the  faeces.  In  the  discharges  of  a  patient 
suffering  with  diabetes,  Fles,  forty  years  ago,  found 
well-preserved  striated  muscle-fibres,  and  the  administra- 
tion of  an  extract  made  from  the  pancreas  of  a  calf 
caused  their  disappearance.  Advanced  chronic  inter- 
stitial pancreatitis  with  atrophy  was  found  at  autopsy. 
Similar  impairment  of  proteid  digestion  has  been  not 
infrequently  noted  in  cases  of  pancreatic  disease,  and 
in  a  few  instances  this  disturbance  has  been  tested  by 
quantitative  methods.  In  cases  of  diabetes  possibly 
due  to  lesions  of  the  pancreas  Hirschfeld  recovered  in 
the  faeces  as  much  as  thirty-two  per  cent,  of  the  nitro- 
genous material  ingested  with  the  food.  In  a  case  of 
Weintraud,  where  autopsy  demonstrated  the  presence 
of  ad\anced  chronic  interstitial  pancreatitis,  forty-five 
and    two-tenths    per    cent,    of    proteids     ingested    re- 


314  DISEASE    OF   THE    PANCREAS. 

appeared  in  the  faeces.     A  similar  case  has  been  re- 
ported by  Zoja. 

SahH  has  devised  a  means  by  which  he  is  able,  he 
believes,  to  test  the  efficiency  of  proteid  digestion  in 
the  intestine.  Gelatin  capsules  hardened  in  formalin 
are  almost  unaffected  by  gastric  digestion,  but  are  dis- 
solved by  pancreatic  juice.  If  such  a  capsule  is  filled 
with  iodoform,  the  urine  or  saliva  o-ives  a  reaction  for 
iodine  at  the  end  of  from  four  to  eight  hours.  Absence 
of  reaction,  or  its  delayed  appearance,  indicates,  accord- 
ing to  Sahli,  an  impairment  of  pancreatic  digestion, 
provided  the  mobility  of  the  stomach  is  normal. 

As  early  as  1820  Kunzmann  observed  the  presence 
of  fat  in  the  fcEces  of  a  man  who  subsequently  died  with 
obstruction  of  the  duct  of  Wirsung-  and  induration  of 
the  pancreas,  together  with  chronic  jaundice.  Fles, 
nearly  fifty  years  later,  described  the  case  of  a  diabetic 
whose  faeces  contained  abundant  fat ;  when  an  emulsion 
made  from  the  pancreas  of  a  calf  was  administered,  fat 
disappeared  from  the  stools.  In  this  case  no  jaundice 
was  present.  A  considerable  number  of  similar  cases 
have  been  described,  but  in  many  other  instances  of 
grave  pancreatic  disease  no  decrease  in  the  absorption 
of  fat  has  been  observed.  Finding  jaundice  associated 
with  pancreatic  disease  in  many  cases  where  fatty  evacu- 
ations have  indicated  impaired  assimilation  of  fat,  Miiller 
has  attributed  the  symptom  to  coexisting  obstruction  of 
the  common  bile  duct.     Nevertheless,  experimental  as 


SYMPTOMS   AND   TREATMENT.  315 

well  as  clinical  observations  leave  little  doubt  that  stea- 
torrhoea  may  follow  loss  of  the  pancreatic  secretion. 

In  some  cases  of  pancreatic  disease,  according  to 
Oser,  fat  is  discharged  with  the  faeces  as  an  oily,  yellow 
fluid,  and  the  condition  may  be  designated  a  true 
steatorrhcea.  In  other  cases  the  faeces  are  clay-colored 
or  grayish-white,  and  the  increased  quantity  of  fat  is 
demonstrable  only  by  microscopic  or  chemical  examina- 
tion ;  such  stools  contain  neutral  fats,  fatty  acids,  and 
soaps. 

An  abnormally  large  amount  of  fat  in  the  intestinal 
discharges  is,  however,  by  no  means  characteristic  of  pan- 
creatic disease,  and  may  even  appear  in  healthy  indi- 
viduals after  the  ingestion  of  very  great  quantities  of 
fat.  The  bile,  it  is  well  known,  is  essential  to  normal 
digestion  of  fats,  and  occlusion  of  the  bile  duct  is  a  fre- 
quent cause  of  fatty  stools.  Moreover,  the  absorption 
of  fat  is  prevented  by  certain  diseases  of  the  intestine, — 
for  example,  by  tuberculosis,  by  tuberculosis  of  the  mes- 
enteric glands,  and  even,  according  to  Nothnagel,  by 
extensive  catarrhal  inflammation  and  other  alterations 
accompanied  by  active  peristalsis.  It  is  only  in  the  ab- 
sence of  such  conditions  that  the  presence  of  fat  is  an 
aid  to  the  diagnosis  of  pancreatic  disease. 

As  a  consequence  of  the  impaired  digestion  which 
results  when  pancreatic  juice  is  lost  or  greatly  dimin- 
ished in  amount,  much  of  the  food  material  taken  into 
the  digestive  tract  passes  through  almost  unchanged. 


3i6  DISEASE    OF   THE    PANCREAS. 

Oser  has  noted  the  voluminous  character  of  the  faecal 
discharges  in  cases  of  pancreatic  disease,  and  has  em- 
phasized the  diagnostic  importance  of  this  symptom. 

Treabnent  of  Pancreatic  Disease. — In  treatises  on 
disease  of  the  pancreas,  such  as  those  of  Friedreich, 
Oser,  and  Lancereaux,  are  mentioned  a  variety  of 
drugs  which  have  been  claimed  to  exert  an  influence 
upon  the  diseased  gland,  but  the  writers  have  no  faith 
in  the  efficacy  of  these  agents.  Alkaline  carbonates, 
pilocarpine,  preparations  of  iron,  of  bismuth,  and  of  mer- 
cury, particularly  calomel,  have  been  believed  to  pro- 
duce beneficial  effects  where  disease  of  the  pancreas 
was  supposed  to  exist.  The  difficulty  with  which  pan- 
creatic disease  is  recognized  presents  an  obstacle  to  the 
establishment  of  an  empirical  therapy,  and  the  evidence 
in  favor  of  these  remedies  has  little  weight. 

Experimental  demonstration  that  diabetes  results 
when  the  pancreas  is  removed  raised  hope  that  the 
disease  might  be  successfully  treated  by  administration 
of  pancreatic  tissue  obtained  from  lower  animals  or  by 
the  use  of  extracts  prepared  from  it.  The  remarkable 
results  which  have  followed  the  use  of  thyroid  extracts 
in  myxodema — a  disease  dependent  upon  destruction 
of  the  thyroid  gland — have  suggested  such  a  possibility. 
A  number  of  observers,  Minkowski,  Thiroloix,  and 
others,  soon  found  that  fresh  pancreas  or  extracts  ad- 
ministered to  animals  deprived  of  their  pancreas  failed 
to  influence  the  assimilation  of  sugar,  whether  given  by 


SYMPTOMS   AND   TREATMENT.  317 

mouth  or  Injected  below  the  skin,  into  the  veins,  or 
into  the  peritoneal  cavity.  No  better  success  has  been 
obtained  in  the  treatment  of  diabetes  mellitiis  in  man, 
though  in  a  considerable  number  of  cases  similar 
methods  have  been  employed.  A  few  writers  have 
claimed  that  some  improvement  follows  the  administra- 
tion of  the  fresh  gland  by  mouth  or  the  subcutaneous 
injection  of  extracts,  but  the  influence  upon  glycosuria 
which  they  note  has  been  temporary  and  inconstant, 
and  may  be  referred  to  other  causes.  Hector  Macken- 
zie, Fiirbringer,  P.  W.  Williams,  Hugounencq  and 
Doyon,  Oser,  and  others,  have  found  glycosuria  unin- 
fluenced by  the  same  methods.  Attempts  to  graft  pan- 
creatic tissue  obtained  from  animals  below  the  skin  of 
patients  suffering  with  diabetes  have  been  unsuccessful. 
Better  results  have  in  a  few  instances  attended  efforts 
to  supply  by  artificial  means  a  deficiency  ofi  digestive 
ferments  consequent  upon  disease  of  the  pancreas. 
In  animals  it  has  been  found  possible  by  the  adminis- 
tration of  fresh  pancreas  to  increase  the  assimilation 
of  proteids  and  fats  impaired  by  extirpation  of  the 
pancreas.  Abelmann  found  that  the  pancreas  of  the 
pig  fed  to  dogs  from  which  the  gland  had  been  re- 
moved aids  the  absorption  of  fat,  and  so  favors  the 
digestion  of  proteids  that  now  seventy-eight  per  cent, 
are  absorbed  instead  of  forty-four  per  cent.  These 
observations  have  been  confirmed  by  Sandmeyer, 
Rosenberg,  and  others. 


3i8  DISEASE   OF   THE   PANCREAS. 

The  remarkable  case  of  Fles  quoted  by  Friedreich 
has  already  been  mentioned  ;  disturbed  digestion  of 
proteids  and  fat  was  associated  with  diabetes  mellitus. 
The  fresh  pancreas  of  a  calf  was  rubbed  in  a  mortar 
with  six  ounces  of  water  and  the  mixture  strained.  A 
part  of  the  milky  fluid  obtained  was  taken  after  each 
meal,  so  that  one  pancreas  was  consumed  daily. 
Though  the  patient  continued  upon  his  previous  diet 
of  bacon  and  fat  meat,  at  the  end  of  two  days  all  fat 
had  disappeared  from  the  faeces  and  the  number  of  un- 
digested muscle-fibres  was  greatly  diminished.  When- 
ever the  administration  of  the  infusion  was  discontinued 
fat  and  muscle-fibres  reappeared.  Although  glycosu- 
ria persisted  unchanged,  the  general  condition  of  the 
patient  improved  for  a  time,  but  death  finally  occurred 
as  the  result  of  phthisis.  The  pancreas  was  the  seat  of 
advanced  sclerosis. 

In  a  case  recorded  by  Langdon-Downs  fatty  diar- 
rhoea was  controlled  by  the  use  of  pancreatic  ex- 
tract ;  the  urine  contained  a  trace  of  sugar,  but  the 
condition  of  the  pancreas  could  not  be  learned  with 
certainty.  Oser  describes  a  case  in  which  a  tumor 
mass  felt  in  the  epigastrium  was  accompanied  by  jaun- 
dice ;  in  the  fseces  were  found  undigested  muscle-fibres 
and  fat.  A  diagnosis  of  carcinoma  of  the  pancreas 
was  made.  The  administration  of  pancreatin  (Merck), 
one  gramme  every  day,  taken  in  divided  doses,  was  fol- 


SYMPTOMS   AND   TREATMENT.  319 

lowed  by  well-marked  improvement  in  the  digestion  of 
fat  and  the  patient  felt  stronger. 

The  few  cases  cited  suggest  that  pancreatic  extracts 
may  be  successfully  used  when  there  is  evidence  that 
digestion  suffers  from  deficiency  of  the  pancreatic 
secretion.  When  the  lesion  is  caused  by  malignant 
growth  or  is  associated  with  diabetes,  though  perma- 
nent benefit  cannot  result,  it  may  be  possible  to 
strengthen  the  patient  and  retard  emaciation. 

Clinical  Significance  of  Fat  Necrosis.  —  The  lesion 
known  as  focal  fat  necrosis  has  been  previously  shown 
to  be  caused  by  penetration  of  the  secretion  of  the 
pancreas  into  the  tissues  about  the  organ,  and  results 
when  the  fat-splitting  ferment  of  the  pancreatic  juice 
comes  into  contact  with  the  living  fat  tissue.  Occlusion 
of  the  pancreatic  duct  favors  the  dissemination  of  fer- 
ments elaborated  by  the  gland,  and  wide-spread  necrosis 
implicating  subcutaneous  and  pericardial  fat  as  well  as 
that  of  the  abdomen  follows  ligation  of  the  pancreatic 
ducts  in  the  cat.  In  human  cases  widely-disseminated 
fat  necrosis  seldom  results  from  occlusion  of  the  pan- 
creatic ducts.  Obstruction  occurs  gradually,  and  is 
associated  with  chronic  interstitial  inflammation  which 
apparently  retards  the  diffusion  of  the  pancreatic  secre- 
tion, so  that  minute  foci  occur  only  in  the  immediate 
neighborhood  of  the  gland. 

Disseminated    necrosis    of    fat    in    most    instances 


320  DISEASE    OF   THE    PANCREAS. 

accompanies  acute  hemorrhagic  pancreatitis,  or  its  later 
stage,  so-called  gangrenous  inflammation.  In  discuss- 
ing the  etiology  of  acute  hemorrhagic  pancreatitis  it  has 
been  shown  that  the  lesion  is  in  many,  if  not  in  all, 
cases  caused  by  a  gall-stone  lodged  at  the  duodenal 
orifice  of  the  diverticulum  of  Vater.  Not  only  is  the 
outflow  of  pancreatic  juice  prevented,  but  bile  is 
injected  into  the  pancreatic  duct  by  the  gall-bladder. 
As  a  result  necrosis  of  the  pancreatic  parenchyma 
ensues,  and  whatever  pancreatic  secretion  may  be 
present,  forced  backward  into  the  tissues  about  the 
organ,  causes  necrosis  of  the  surrounding  fat.  The 
lesion  more  rarely  accompanies  suppurative  inflamma- 
tion of  the  gland. 

By  some  writers  fat  necrosis  has  been  described  as  a 
disease  entity  associated  with  certain  more  or  less  ill- 
defined  symptoms.  The  condition,  on  the  contrary,  is 
always  a  consequence  of  pancreatic  disease  and,  as 
previously  pointed  out,  bears  much  the  same  relation 
to  lesion  of  the  pancreas  as  does  jaundice  to  hepatic 
disease.  Its  presence  gives  evidence  that  the  pancre- 
atic secretion  has  been  diverted  from  its  normal  chan- 
nels into  the  interstitial  tissue  of  the  organ  and  into 
the  neighboring  fatty  tissue. 

In  a  case  cited  by  Hansemann,  foci  of  necrosis  oc- 
curred in  the  subcutaneous  tissue,  and  their  presence 
was  marked  by  circumscribed  injection  of  the  overlying 
skin.     Rarely,  however,  does  the  lesion  affect  adipose 


SYMPTOMS  AND  TREATMENT.        321 

tissue  outside  of  the  abdomen,  and  during  life  is  recog- 
nizable only  when  the  peritoneal  cavity  is  opened. 
Since  in  every  instance  disseminated  fat  necrosis  indi- 
cates the  existence  of  grave  disease  of  the  pancreas,  its 
recognition  is  of  importance  to  the  surgeon  who  opens 
the  abdominal  cavity.  Particularly  is  this  true  when 
pancreatic  disease  has  been  unsuspected  and  operation 
has  been  undertaken,  perhaps  with  the  purpose  of  reliev- 
ing intestinal  obstruction  suggested  by  the  symptoms. 
With  few  exceptions  disseminated  fat  necrosis  encoun- 
tered at  operation  gives  evidence  that  the  pancreas 
is  the  seat  of  acute  hemorrhagic  inflammation  or  of 
secondary  gangrenous  change. 

Foci  of  necrotic  fat  are  very  conspicuous  by  reason 
of  their  homogeneous,  opaque,  yellowish-white  color,  in 
marked  contrast  to  the  surrounding  translucent  yellow 
fat,  and  when  the  omentum  is  exposed  it  is  unlikely 
that  they  will  be  overlooked  if  present.  To  one  who 
has  seen  the  lesion  it  is  unmistakable,  but  to  the  inex- 
perienced miliary  tubercles  or  carcinomatous  nodules 
may  be  suggested  by  the  shape  and  color  of  the  sharply- 
defined  areas.  The  lesion,  however,  is  not  elevated  and 
nodule-like,  but  on  examination  is  found  to  represent  a 
transformation  of  the  pre-existing  fat. 

When  the  outflow  of  bile  is  hindered  and  jaundice 
occurs,  biliary  pigments  make  their  appearance  in  the 
urine.  Abundant  evidence  collected  in  Chapter  V.  has 
shown  that  fat  necrosis  is  due  to  the  action  of  the  fat- 


322 


DISEASE   OF   THE    PANCREAS. 


splitting  ferment  secreted  by  the  pancreas,  and  this  fer- 
ment has  been  found  by  Flexner  in  the  areas  of  necrosis. 
The  possibility  suggests  itself  that  the  ferment  which  is 
free  in  the  tissue  may  be  excreted  by  the  kidneys, 
though  it  is  not  improbable  that  the  acidity  of  the  urine 
may  partially  or  completely  destroy  its  activity. 

I  have  examined  the  urine  in  one  instance  of  acute 
hemorrhagic  pancreatitis  (Case  IV.),  and  the  result, 
though  not  conclusive,  is  cited  in  order  that  its  accuracy 
may  be  further  tested.  The  method  employed  is  that  de- 
scribed by  Castle  and  Loevenhart ;  ethyl  butyrate  care- 
fully purified,  when  acted  upon  by  a  fat-splitting  ferment, 
is  decomposed  with  the  formation  of  butyric  acid,  which 
gives  an  acid  reaction  to  the  solution. 

Following  the  operation  which  was  performed  in  Case  IV.  the 
patient  voided  no  urine,  and  in  the  bladder  at  autopsy  was  found 
only  a  small  quantity.  After  adding  a  few  drops  of  litmus  solution, 
this  was  neutralized  with  potassium  hydroxide  (one-tenth  normal 
solution)  and  divided  into  two  parts.  To  one  part  was  added  a  few 
drops  of  ethyl  butyrate.  The  second  part,  used  as  a  control,  was 
boiled  in  order  to  destroy  the  ferment,  if  present,  and  ethyl  butyrate 
was  added.  Both  specimens  were  kept  at  37°  C,  and  at  the  end 
of  twenty-four  hours  the  unboiled  specimen  had  acquired  a  well- 
marked  acid  reaction,  while  the  control  specimen  was  unchanged. 
Owing  to  the  small  quantity  of  urine  obtained  it  was  not  possible  to 
repeat  the  test. 

Recognition  in  the  urine  of  a  ferment  derived  from 
the  pancreas  would  afford  a  certain  means  for  the  diag- 


SYMPTOMS   AND   TREATMENT.  323- 

nosis  of  obscure  pancreatic  affections  accompanied  by 
fat  necrosis,  notably  acute  hemorrhagic  pancreatitis. 
Hence  it  is  desirable  to  apply  in  suspected  cases  the 
test  just  described  in  order  if  possible  to  establish  its 
value. 

Symptoms  of  Acute  Hemorrhagic  Pancreatitis. — The 
difficulty  of  diagnosis  characteristic  of  disease  of  the  pan- 
creas is  well  illustrated  by  acute  hemorrhagic  pancrea- 
titis, yet  the  clinical  picture  which  it  presents  is  often 
distinctive,  and  in  many  instances  recognition  of  the 
condition  is  possible. 

This  lesion,  in  a  large  proportion  of  cases  at  least, 
is  a  consequence  of  cholelithiasis  and  is  caused  by  the 
action  of  bile  diverted  into  the  pancreatic  duct  by  a 
small  calculus  lodged  at  the  duodenal  orifice  of  the 
diverticulum  of  Vater.  Wide-spread  necrosis  of  the 
parenchyma  ensues  and  is  associated  with  abundant 
hemorrhage  into  and  about  the  organ.  Inflammatory 
changes  rapidly  follow,  and  death  frequently  occurs 
within  forty-eight  hours  after  the  onset  of  the  symptoms. 
In  a  considerable  number  of  cases  the  individual  sur- 
vives, and  the  necrotic  pancreas,  becoming  black  and 
softened,  assumes  the  appearance  described  as  gangre- 
nous, so-called  gangrenous  pancreatitis  representing  a 
like  stage  of  the  hemorrhagic  lesion.  Bacteria  invade 
the  dead  tissue,  and  inflammation  of  the  adjacent  peri- 
toneum not  infrequently  results  in  the  formation  of  an 
abscess  cavity  limited  to  the  lesser  peritoneum. 


324  DISEASE    OF   THE    PANCREAS. 

Fitz  describes  as  follows  the  symptoms  of  acute 
hemorrhagic  pancreatitis  :  "  It  begins  with  intense  pain, 
especially  in  the  upper  abdomen  ;  soon  followed  by 
vomiting,  which  is  likely  to  be  more  or  less  obstinate, 
and  not  infrequently  by  slight  epigastric  swelling  and 
tenderness,  with  obstinate  constipation.  A  normal  or 
subnormal  temperature  may  be  present,  and  symptoms 
of  collapse  precede,  by  a  few  hours,  death,  which  is  most 
likely  to  occur  between  the  second  and  fourth  days." 

Since  the  lesion  is  caused  by  the  lodgement  of  a  gall- 
stone at  the  duodenal  orifice  of  the  bile  duct,  symptoms 
of  biliary  colic  may  precede  those  of  the  pancreatic 
lesion  and  may  be  confounded  with  them.  The 
intensity  of  the  pain,  its  diffuse  epigastric  character, 
with  occasional  localization  on  the  left  side,  and  the 
profound  collapse  usually  present,  according  to  Thayer, 
give  sufficient  evidence  that  the  pancreas  is  implicated. 
Acute  hemorrhagic  pancreatitis  is  frequently  mistaken 
for  intestinal  obstruction,  but  the  intensity  and  localiza- 
tion of  the  pain,  the  severity  of  the  collapse,  and  the 
absence  of  stercoraceous  vomitinor  in  most  instances 
serve  to  characterize  the  condition. 

The  profound  collapse  and  rapidly  fatal  termination 
of  many  cases  of  acute  hemorrhagic  pancreatitis  suggest 
the  presence  of  an  acute  intoxication.  A  similar  con- 
dition follows  the  lesion  produced  experimentally  in 
dogs,  and  death  within  twenty-four  hours  may  be 
caused  by  the  injection  of  five  cubic  centimetres  of  bile 


SYMPTOMS  AND  TREATMENT.        325 

into  the  pancreatic  duct.  Bile,  doubtless  in  association 
with  the  pancreatic  secretion  acting  upon  the  substance 
of  the  gland,  produces,  both  in  the  human  and  in  the 
experimental  cases,  substances  which,  when  absorbed, 
exert  a  profoundly  poisonous  action.  Such  an  explana- 
tion of  the  fatal  result  appears  more  probable  than  that 
which  seeks  to  refer  the  symptoms  of  collapse  or  shock 
to  an  obscure  lesion  of  the  sympathetic  ganglia  near 
the  pancreas. 

In  many  instances  the  symptoms  of  onset  are  much 
less  severe  than  those  just  described,  and  perhaps, 
associated  with  an  attack  of  gall-stone  colic,  may  be  so 
slight  as  to  be  unrecognizable.  The  patient  survives 
and  the  disease  pursues  a  more  or  less  chronic  course. 
The  symptoms  are  essentially  those  previously  men- 
tioned, but  they  occur  with  less  intensity.  Pain  is 
localized  in  the  epigastrium,  and  vomiting  may  recur  at 
intervals.  Symptoms  indicative  of  suppuration  finally 
give  evidence  that  the  necrotic  tissue  of  the  pancreas 
has  become  infected  ;  there  is  an  irregular  temperature, 
and  leucocytosis  suggests  the  presence  of  an  abscess. 
An  ill-defined  tumor  felt  above  the  umbilicus  gives 
more  positive  proof  that  fluid  has  accumulated  about 
the  pancreas  in  the  lesser  peritoneal  cavity.  The 
appearance  of  such  a  mass  in  the  epigastric  region  is 
due,  not  to  the  enlarged  pancreas,  which  is  rarely  if 
ever  palpable,  but  to  the  presence  of  hemorrhagic  or 
purulent  fluid  about  the  organ. 


326  DISEASE    OF    THE    PANCREAS. 

Those  disturbances  of  dig-estion  which  have  been 
noted  in  describing  the  general  symptomatology  of 
pancreatic  disease  may  occur,  but  rarely  is  there  such 
complete  destruction  of  the  pancreas  that  its  functional 
activity  is  wholly  destroyed.  In  Case  I.  and  in  Case 
XXXIII.,  to  be  described,  the  patient  passed  clay- 
colored  stools. 

In  only  two  of  forty-one  cases  of  hemorrhagic  pan- 
creatitis, and  in  but  three  of  forty  cases  of  gangren- 
ous inflammation  collected  by  Korte,  was  sugar  present 
in  the  urine.  The  following  interesting  case  of  diabetes 
consequent  upon  acute  hemorrhagic  pancreatitis  has 
been  recently  described  by  Franke.  The  patient,  a  man 
aged  forty-two  years,  who  had  previously  enjoyed  good 
health,  was  attacked  twelve  days  before  his  death  with 
severe  abdominal  pain,  accompanied  by  vomiting.  The 
pain,  which  was  localized  in  the  region  of  the  umbilicus, 
continued,  and  the  patient  complained  much  of  thirst. 
When  seen,  eight  days  after  the  onset  of  symptoms, 
sugar  was  found  in  the  urine,  and  to  the  amount  of  3.5 
per  cent,  was  present  until  death.  The  fat  below  the 
parietal  peritoneum,  the  fat  of  the  omentum,  of  the 
mesentery,  and  of  the  mediastinum  as  well,  contained 
numerous  foci  of  necrosis.  The  pancreas  was  repre- 
sented by  a  large  blackish-red  mass,  which  consisted  in 
great  part  of  altered  blood,  but  in  a  few  places  still  pre- 
served a  lobular  structure.  The  gall-bladder  was  dis- 
tended and  contained  a  calculus  about  the  size  of  a 
plum. 


SYMPTOMS  AND  TREATMENT.        327 

Acute  hemorrhagic  and  gangrenous  pancreatitis  being 
caused  by  the  lodgement  of  a  gall-stone  in  the  diver- 
ticulum of  Vater,  patients  suffering  with  this  disease  not 
infrequently  give  a  history  of  preceding  gall-stone 
colic.  In  Case  I.  the  patient  underwent  an  attack  of 
jaundice  six  months  before  his  fatal  illness.  In  other 
instances  there  has  been  a  history  of  repeated  par- 
oxysms of  severe  abdominal  pain,  doubtless  due  to 
the  passage  of  calculi  which  have  failed  to  lodge  at  the 
orifice  of  the  bile  duct.  Precedino-  attacks  of  so-called 
gastric  or  gastro-duodenal  dyspepsia,  noted  by  Fitz, 
in  some  cases  at  least  admit  of  a  similar  explanation. 

In  some  reported  cases  recurrent  pancreatitis  has 
been  described,  but  attacks  of  severe  pain  and  vomiting 
preceding  the  fatal  illness  are  doubtless  often  referable 
to  cholelithiasis.  Nevertheless,  it  cannot  be  denied 
that  acute  pancreatitis  may  recur,  for  should  the  patient 
survive  a  primary  attack,  the  structure  of  the  divertic- 
ulum of  Vater  being  favorable,  a  second  might  follow 
the  expulsion  of  another  stone  of  appropriate  size. 

Treatinejit  of  Acute  Hemorrhagic  and  Gangrenous 
Pancreatitis. — What  has  been  said  concerning  the  eti- 
ology and  pathology  of  acute  inflammation  of  the  pan- 
creas demonstrates  the  futility  of  medical  treatment 
directed  to  the  palliation  of  the  lesion.  At  the  onset  of 
symptoms  the  attention  of  the  physician  will  be  di- 
rected to  the  profound  collapse,  and  efforts  will  be 
made  to  strengthen  the  enfeebled  circulation.     The  in- 


328  DISEASE   OF   THE    PANCREAS. 

tense  abdominal  pain  is  often  uncontrollable  by  the 
use  of  morphia.  For  the  continued  vomiting  Korte 
recommends  that  the  stomach  be  washed  out,  food 
by  mouth  discontinued,  and  nutrient  and  stimulating- 
enemata  resorted  to. 

It  is  only  by  surgical  means  that  the  seat  of  the 
disease  can  be  reached.  When  it  is  possible  to  make 
a  diagnosis  of  acute  hemorrhagic  pancreatitis  from  the 
symptoms  which  in  a  certain  number  of  cases  are 
sufficiently  characteristic,  the  advisability  of  operation 
presents  itself  for  consideration.  During  the  primary 
collapse  little  is  to  be  gained  by  interference  which 
would  further  impair  the  resistance  of  the  patient  ; 
hemorrhage  is  rarely  profuse  and  bears  little  relation 
to  the  severity  of  the  condition.  Should  the  individual 
survive  the  early  symptoms  of  shock,  infection  of  the 
gangrenous  tissue  and  abscess  formation  limited  to  the 
lesser  peritoneal  cavity  soon  demand  exploration  and 
drainage.  Septic  fever,  leucocytosis,  and  the  presence 
of  a  palpable  mass  in  the  epigastrium  indicate  the 
necessity  for  operative  interference. 

In  some  cases  symptoms  are  so  indefinite  that  acute 
hemorrhagic  pancreatitis  is  not  suspected,  while  in 
other  instances,  though  such  a  lesion  suggests  itself,  the 
evidence  is  insufficient  to  exclude  the  presence  of  other 
conditions.  Experience  has  shown  that  the  disease  is 
often  first  recognized  by  the  presence  of  fat  necrosis 
noted  at  operation  undertaken  for  the  relief  of  a  sup- 


SYMPTOMS  AND  TREATMENT.        329 

posed  intestinal  obstruction  or  perhaps  performed  for 
the  purpose  of  exploration  demanded  by  continued 
symptoms  of  grave  abdominal  disorder. 

Should  disseminated  fat  necrosis  indicate  the  pres- 
ence of  a  pancreatic  lesion,  exploration  of  the  lesser 
peritoneal  cavity  through  the  gastrocolic  omentum  may 
disclose  the  presence  of  a  pancreatic  or  peripancreatic 
abscess  and  permit  its  evacuation.  Thick  abdominal 
walls  and  omental  fat  in  large  quantity,  together  with 
an  accumulation  of  necrotic  tissue  and  partially  clotted 
blood  within  the  lesser  peritoneal  cavity,  at  times  make 
access  to  the  pancreas  itself  difficult  or  impossible,  at 
least  undesirable. 

During  whatever  stage  of  the  disease  operation  is 
performed  the  condition  of  the  bile  passages  is  impor- 
tant and  may  offer  an  imperative  indication  for  interfer- 
ence. The  common  bile  duct  should  be  examined  so 
far  as  it  is  possible,  and  bearing  in  mind  the  mechanism 
by  which  a  small  calculus  may  produce  the  lesion,  the 
operator  should,  if  feasible,  exclude  the  possibility  that  a 
stone  is  still  lodged  in  the  diverticulum  of  Vater.  If 
such  impaction  should  be  found,  removal  of  the  calculus 
is  essential  in  order  to  prevent  further  destruction  of 
the  pancreas.  The  temporary  lodgement  of  a  calculus 
within  the  diverticulum  may  produce  an  extensive  pan- 
creatic lesion,  yet,  finally  expelled  into  the  duodenum, 
the  stone  may  be  no  longer  demonstrable  either  at 
operation    or   at   autopsy.     Hence    in    a    considerable 


330 


DISEASE    OF   THE    PANCREAS. 


number  of  cases  the  gall-bladder  will  be  found  to  be 
filled  with  gall-stones,  even  though  the  bile  ducts  are 
free.  These  stones  may  be  of  such  size  that  any  one 
of  them  lodged  at  the  orifice  of  the  common  duct  might 
divert  bile  into  the  pancreatic  duct.  In  Case  I.  the  gall- 
bladder was  distended  with  small  tetragonal  calculi, 
each  about  the  size  of  a  pea  (see  Fig.  12,  p.  102). 

In  a  patient  with  acute  pancreatitis  and  fat  necrosis, 
operated  upon  by  Dr.  Howard  A.  Kelly,  recovery  fol- 
lowed the  removal  of  a  large  number  of  small  gall- 
stones from  the  gall-bladder.  Dr.  Kelly  has  kindly 
permitted  me  to  add  the  following  notes  of  this  case, 
which  will  be  published  in  detail  by  Dr.  Louis  Lehr. 

Case  XXXIII. — Mrs.  W.,  aged  forty-one  years,  was  admitted  to 
the  care  of  Dr.  Kelly,  May  17,  1902.  For  several  years  preceding, 
at  intervals  of  almost  every  two  months,  she  had  suffered  with  attacks 
of  pain  in  the  epigastrium.  Her  present  illness  began  one  week 
before  with  severe  pain  in  the  left  side  and  back,  lasting  about  three 
days,  and  subsequently  recurring  in  paroxysms,  which  necessitated  the 
use  of  morphia.  There  was  slight  nausea,  but  no  vomiting.  The  stools 
were  clay  colored  and  of  very  foul  odor ;  the  temperature  varied 
from  98°  to  100°  F.  An  operation  was  undertaken  on  the  tenth  day 
of  her  illness.  After  an  incision  had  been  made  through  the  thick 
abdominal  wall,  the  omentum  was  found  to  contain  opaque,  white  foci 
of  fat  necrosis.  An  oblong  mass  about  nine  centimetres  in  length  and 
six  centimetres  broad  lying  behind  the  greater  curvature  of  the  stom- 
ach occupied  the  position  of  the  pancreas.  Further  examination 
was  not  possible  on  account  of  the  great  quantity  of  fat.  The  gall- 
bladder was  found  partially  collapsed  about  a  large  number  of  small 


^  •  •  "^  # 

• 

#       10  H  ^  '^  ' 

Fig.  21. — Calculi  which  in  Case  XXXIII.  were  at  operation  removed  from  the 
gall-bladder;  compare  with  Fig.  12,  p.  102. 


SYMPTOMS  AND   TREATMENT. 


331 


gall-stones.  An  incision  was  made  through  the  skin  and  abdominal 
wall  opposite  the  gall-bladder  ;  the  organ  was  stitched  to  the  edges 
of  the  wound  and  opened.  About  fifty  small  calculi  of  almost  uni- 
form size  were  removed  (see  Fig.  21).  The  wound  opposite  the  gall- 
bladder healed  slowly,  and  the  patient  made  an  uneventful  recovery. 

In  the  preceding'  case  acute  hemorrhagic  pancreatitis 
and  consequent  fat  necrosis  was  doubtless  caused  by 
the  passage  of  a  small  calculus  similar  to  those  so 
numerous  in  the  gall-bladder.  These  stones  differed 
but  little  from  those  which  filled  the  o-all-bladder  in 
Case  I.,  and  were  of  the  same  uniform  size.  The  clinical 
history  makes  it  probable  that  similar  calculi  had  been 
repeatedly  expelled  previous  to  the  attack  for  which 
operation  was  performed,  but  impaction  in  the  divertic- 
ulum of  Vater  had  failed  to  occur.  Removal  of  those 
still  present  in  the  gall-bladder  offered  the  best  assur- 
ance of  immunity  from  subsequent  attacks. 

Symptoms  of  Chronic  Pancreatitis. — Chronic  pancrea- 
titis is  rarely  accompanied  by  such  definite  symptoms 
that  its  recognition  is  possible  during  life.  In  most  in- 
stances a  considerable  part  of  the  parenchyma  is  unde- 
stroyed,  and  is  capable  of  performing,  in  part  at  least, 
the  functions  of  the  gland.  Hence  chronic  pancreatitis 
may  be  unaccompanied  by  glycosuria  or  by  any  disturb- 
ance of  digestion.  Since  chronic  pancreatitis  usually 
accompanies  grave  disturbances  of  the  stomach,  duo- 
denum, or  bile  passages,  symptoms  of  the  primary  dis- 
order are  predominant  and  hinder  recognition  of  the 


332 


DISEASE    OF   THE    PANCREAS. 


pancreatic  lesion.  On  the  other  hand,  disease  of  neigh- 
boring organs  may  suggest  the  presence  of  chronic  pan- 
creatitis. 

From  the  cHnical  stand-point  it  is  desirable  to  distin- 
guish between  an  interlobular  and  an  interacinar  type 
of  chronic  interstitial  pancreatitis.  The  first  is  rarely 
accompanied  by  diabetes  mellitus ;  the  latter,  affect- 
ing both  secreting  parenchyma  and  interacinar  islands, 
except  in  its  earliest  stage,  is  associated  with  diabetes. 

The  etiology  of  chronic  interstitial  pancreatitis  has 
been  previously  discussed  in  detail.  The  disease  is 
uncommon  in  early  life,  and  two-thirds  of  the  cases 
occur  between  the  ages  of  forty  and  sixty  years. 
Chronic  pancreatitis  follows  a  variety  of  readily  recog- 
nizable conditions  affecting  other  organs,  and  hence 
its  existence  may  be  not  infrequently  suspected. 

Chronic  pancreatitis  of  the  interlobular  type  in  the 
greatest  number  of  cases  is  caused  by  obstruction  of 
the  duct  produced  by  pancreatic  calculi,  by  biliary  cal- 
culi, or  by  tumors  and  cysts  compressing  the  duct  as  it 
passes  through  the  head  of  the  gland.  In  many  such 
cases  disturbances  of  digestion  consequent  upon  loss 
of  the  pancreatic  secretion  have  been  noted.  Acute 
and  chronic  inflammation  of  the  stomach  and  duode- 
num on  the  one  hand,  and  of  the  bile  passages  on  the 
other,  may,  as  in  cases  previously  described,  be  accom- 
panied by  interlobular  pancreatitis,  the  result  of  an 
ascendinor  infection.     I   have   described   four    cases   in 


SYMPTOMS   AND   TREATMENT.  333 

which  chronic  interlobular  inflammation  was  found  at 
autopsy  in  individuals  who  had  suffered  with  persistent 
vomiting,  caused  doubtless  in  three  cases,  presumably 
in  all,  by  lesions  of  the  stomach  or  of  the  duodenum. 

Interlobular  pancreatitis  is  accompanied  by  diabetes 
only  when  the  lesion  is  so  far  advanced  that  dense 
sclerotic  tissue,  which  replaces  the  secreting  paren- 
chyma, surrounds  and  compresses  the  islands  of  Lan- 
gerhans.  Glycosuria  was  noted  in  only  one  of  my 
twent}^-two  cases.  In  this  case  chronic  interstitial  pancre- 
atitis was  caused  by  calculi  obstructing  the  pancreatic 
ducts  ;  glycosuria  was  of  mild  type,  and  disappeared 
when  the  patient  was  given  a  diet  poor  in  carbohydrates. 

In  at  least  five  of  fifteen  cases  in  which  Wille  found 
alimentary  glycosuria,  chronic  inflammation — from  his 
description  presumably  of  the  interlobular  type — was 
found  at  autopsy.  It  is  not  improbable  that,  even  though 
the  lesion  does  not  implicate  the  islands  of  Langerhans, 
chronic  inflammatory  changes  in  their  neighborhood 
may  slightly  impair  their  functional  activity,  perhaps  by 
interfering  with  their  blood  supply.  Where  chronic 
pancreatitis  is  suspected,  the  presence  of  ahmentary 
glycosuria,  tested  by  the  administration  of  sugar,  would 
give  additional  evidence. 

Distinctive  of  the  interacinar  form  of  chronic  pan- 
creatitis are  glycosuria  and  other  symptoms  of  diabetes 
mellitus.  Diabetes  mellitus,  however,  is  caused  by 
other  lesions  of  the  pancreas,   and  indeed  may  occur 


334 


DISEASE    OF   THE    PANCREAS. 


in  the  absence  of  pancreatic  disease.  In  nine  of  nine- 
teen cases  of  diabetes  which  I  examined  at  autopsy 
interacinar  pancreatitis  occurred  ;  in  six  of  these 
cases  hyaline  changes  were  also  present.  Although 
no  group  of  symptoms,  as  Lancereaux  has  claimed,  is 
characteristic  of  diabetes  caused  by  pancreatic  lesion, 
conditions  associated  with  the  disease  may  give  evi- 
dence that  it  accompanies  interacinar  inflammation  of 
the  o-land. 

In  a  considerable  number  of  cases  previously  cited 
from  the  literature  arterial  sclerosis  has  been  associated 
with  chronic  interstitial  inflammation  of  the  pancreas. 
In  one  of  the  cases  included  in  my  series  advanced 
arterial  sclerosis  in  a  diabetic  was  followed  by  gangrene 
of  the  legs,  and  at  autopsy  chronic  interacinar  pancrea- 
titis was  found.  Where  advanced  arterial  sclerosis  ac- 
companies diabetes  mellitus,  the  latter  disease  is  with 
much  probability  referable  to  interacinar  inflammation  of 
the  pancreas. 

The  association  of  diabetes  mellitus  and  cirrhosis  of 
the  liver  has  been  very  frequently  observed,  and  in 
some  of  these  cases  examined  at  autopsy  the  pancreas 
has  been  found  to  be  the  seat  of  chronic  inflammatory 
changes.  Chronic  inflammation  of  the  pancreas  and 
of  the  liver  is  doubtless  in  such  cases  dependent  upon 
the  same  etiological  factors.  In  Cases  X.  and  XL 
(pages  1 80  and  181)  diabetes  and  atrophic  cirrhosis 
coexisted,  while  at  autopsy  chronic  pancreatitis  of  the 


SYMPTOMS  AND  TREATMENT.        335 

interacinar  type  was  demonstrable.  I  am  indebted  to 
Dr.  Libman,  of  New  York,  for  notes  upon  a  similar 
case.  These  observations  ag^ree  with  those  of  Lefas, 
who  found  diffuse  chronic  infiammation  of  the  pancreas 
in  association  with  atrophic  cirrhosis  of  the  liver.  Dia- 
betes with  cirrhosis  of  the  liver  is  with  much  probability 
indicative  of  interacinar  pancreatitis. 

One  form  of  chronic  interacinar  pancreatitis  with 
diabetes  and  cirrhosis  may  be  readily  recognized. 
Diabetes  with  haemochromatosis,  the  so-called  bronzed 
diabetes,  is  doubtless  in  all  cases  the  result  of  chronic 
interacinar  inflammation  affecting  the  pancreas  and 
implicating  the  islands  of  Langerhans.  The  combina- 
tion of  symptoms  in  such  cases  is  characteristic. 
Diabetes  mellitus  is  associated  with  hypertrophic 
cirrhosis  of  the  liver,  and  there  is  often  intense  pig- 
mentation of  the  skin.  When  doubt  exists  as  to  the 
character  of  this  pigmentation,  iron  may  be  demon- 
strated by  appropriate  methods  in  sections  made  from 
a  bit  of  skin,  if  such  is  obtainable  from  the  patient. 
In  a  case  described  by  Anschiitz,  fatty  stools  gave 
evidence  that  the  secretion  of  the  pancreas  was 
diminished  in  amount ;  but  even  in  the  absence  of  such 
symptoms,  diabetes  accompanying  hypertrophic  cirrhosis 
with  pigmentation  may  be  attributed  to  chronic  pancrea- 
titis of  the  interacinar  type. 

Pancreatitis  as  a  Complication  of  other  Diseases. — It 
has  been  repeatedly  stated  that  in  most  instances  both 


336  DISEASE    OF   THE    PANCREAS. 

acute  and  chronic  inflammation  of  the  pancreas  are 
secondary  to  disease  of  other  organs.  Acute  or  chronic 
inflammation  may  be  the  result  of  an  ascending  infection 
of  the  pancreatic  ducts  having  its  origin  in  the  inflamed 
stomach,  duodenum,  or  bile  passages.  The  occurrence 
of  chronic  inflammation  in  association  with  persistent 
vomiting  has  been  emphasized.  The  close  relationship 
between  disease  of  the  liver  and  of  the  pancreas  is 
especially  noteworthy,  chronic  inflammation  of  the  liver 
and  pancreas,  doubtless  due  to  the  same  etiological 
factor,  not  infrequently  occurring  in  conjunction.  Much 
more  common,  however,  is  the  association  of  choleli- 
thiasis and  disease  of  the  pancreas  ;  and  it  is  perhaps 
desirable  to  consider  briefly  the  conditions  under  which 
cholelithiasis  is  accompanied  by  pancreatic  disease, 
even  though  facts  previously  mentioned  be  repeated. 

Whenever  a  gall-stone  is  expelled  from  the  common 
bile  duct,  temporary  occlusion  of  the  pancreatic  duct 
results.  The  mechanism  by  which  a  small  gall-stone 
lodged  at  the  orifice  of  the  diverticulum  of  \''ater  diverts 
bile  into  the  pancreatic  duct  and  causes  hemorrhagic 
pancreatitis  has  been  described  in  detail  ;  a  variety  of 
conditions  must  be  fulfilled  in  order  that  acute  pancre- 
atitis follow  the  passage  of  a  calculus,  and  in  only  a 
small  proportion  of  cases  is  gall-stone  colic  accompanied 
by  acute  disease  of  the  pancreas.  In  not  more  than 
one-third  of  all  individuals  are  the  anatomical  peculiari- 
ties of  the   diverticulum  of  Vater  such  that  a  calculus 


SYMPTOMS   AND   TREATMENT.  ^tZl 

can  occlude  its  duodenal  orifice  yet  fail  to  obstruct 
the  bile  or  pancreatic  ducts  as  they  enter  the  divertic- 
ulum. Even  should  the  diverticulum  be  of  consider- 
able length  and  provided  with  a  narrow  duodenal  orifice 
a  calculus  can  transform  the  two  ducts  into  a  continu- 
ous channel  only  if  it  be  of  very  small  size.  In  many 
instances  the  offending  calculi  have  not  been  larger, 
roughly  speaking,  than  a  pea.  Such  facts  help  to  ex- 
plain the  infrequency  of  acute  hemorrhagic  pancreatitis 
when  compared  with  the  frequency  of  cholelithiasis. 
The  symptoms  which  characterize  acute  hemorrhagic 
pancreatitis  and  distinguish  it  from  uncomplicated 
biliary  colic  have  already  been  mentioned. 

A  large  gall-stone  lodged  in  the  terminal  part  of  the 
common  bile  duct,  or  indeed  within  the  diverticulum  of 
Vater,  prevents  the  escape  of  pancreatic  secretion, 
unless  the  duct  of  Santorini  affords  a  free  outlet,  and 
chronic  interlobular  inflammation  of  the  gland  results. 
The  clinical  importance  of  this  condition  lies  in  the  fact 
that  the  indurated  gland  felt  during  an  operation  under- 
taken for  the  removal  of  gall-stones  in  the  common 
duct  has  been  frequently  mistaken  for  malignant  growth. 
Recognition  of  the  relation  between  cholelithiasis  and 
chronic  pancreatitis  will  have  an  important  influence 
upon  the  prognosis  in  such  cases,  and  removal  of  the 
occluding  calculus  will  prevent  further  development  of 
the  pancreatic  lesion. 


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¥ 

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344 


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150 


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23 


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INDEX. 


Accessory  pancreas,  46 

diverticulum     of     intestine 

with,  47 
in  papilla  of  duct  of  San- 

torini,  43 
origin  of,  57 
within  umbilicus,  49 
Acute  pancreatitis,  varieties  of,  89 

with  diabetes,  252 
Adrenal  gland,  277 
Alcohol,    causing   chronic    pancrea- 
titis, 206 
Alimentary  glycosuria,  238 

as    symptom   of   pancreatic 

disease,  310 
with  acromegaly,  2^^) 
with  cirrhosis,  272 
with    exophthalmic    goitre, 

277 
with  pancreatic  disease,  272 
with  partial  extirpation  of 
the  pancreas,  242 
Amyloid  degeneration,  218 
Annular  pancreas,  46 
Anomalies  of  the  pancreas,  46 
Arterial     sclerosis,     with     chronic 
pancreatitis,    198 
with  diabetes,  271,  334 
with      pancreatic      hemor- 
rhage, 94 
Ascending    infection    of    the    pan- 
creatic ducts,  179,  192 
Asphyxiation,  glycosuria  with,  240 
Atrophy  of  the  pancreas,  cachectic, 
258 
with  diabetes,  253 


Bernard's  puncture,  239 

Bibliography,  339 

Bile,        hemorrhagic        pancreatitis 

caused  by,  121 
Bronzed  diabetes,  289,  335 

Calculi,  pancreatic,  causing  chronic 
pancreatitis,  185 
with  diabetes,  256 
Carbon  monoxide  poisoning,  glyco- 
suria with,  240 
Carcinoma  of  the  pancreas,  causing 
chronic  pancreatitis,  190 
with  diabetes,  252,  256,  309 
Centro-acinar  cells,  69 
Cholelithiasis,     with    chronic    pan- 
creatitis, 188,  ZZ7 
with  fat  necrosis,  155 
with    gangrenous    pancreatitis, 

III 
with   hemorrhagic   pancreatitis, 

40,  100,  329,  336 
with    suppurative    pancreatitis, 
III 
Chronic      interacinar      pancreatitis, 
180 
interlobular  pancreatitis,  173 
interstitial    pancreatitis,    caused 
by  alcohol,  206 
etiology  of,  184 
fat  necrosis  with,    137, 

149,  154,  156 
islands   of   Langerhans 

with,   164 
of   accessory   pancreas, 
56 

355 


156 


INDEX. 


Chronic       interstitial      pancreatitis, 
parapancreatic        fat 
necrosis  with,   i6i 
symptoms  of,  331 
varieties  of,  163,  170 
with  acromegaly,  273 
with  bronzed  diabetes, 

293 
with  carcinoma,   190 
with     chronic     passive 
congestion,  200 
with  cirrhosis,  207 
with  diabetes,  252,  263 
with     duodenal     stric- 
ture, 197 
with  gastritis,  193 
with      hagmochromato- 

sis,  288,  298,  301 

with    infection    of    the 

pancreatic  ducts,   179 

with  obstruction  of  the 

pancreatic  ducts,  173 

with  pancreatic  calculi, 

185 
with  syphilis,  204 
with  tuberculosis,  202 
with  vomiting,  193 
passive       congestion,       causing 
chronic  pancreatitis,  200 
Cirrhosis  of  the  liver,  with  chronic 
pancreatitis,  207 
with  diabetes,  271,  334 
with  hsemochromatosis,  287 
Coagulative    necrosis    of    the    pan- 
creas, 233 
Common  bile   duct,   relation  of,  to 
duct  of  Wirsung,  29, 
38 
relation     of,     to     pan- 
creas, 37 
Cysts  of  the  pancreas,  191,  251,  313 

Development  of  the  pancreas,  21 
in  lower  animals.  22 


Development    of    the    pancreas,    in 
man,  25 
retarded     with     congenital 
syphilis,   169 
Diabetes    mellitus,    as    symptom    of 
pancreatic  disease,  307 
cases  of,  250 
experimental,  241 
metabolism    of    iron    with, 

297 
pathology  of,  237,  278 
relation  of  islands  of  Lan- 

gerhans  to,  261 
treatment  of,  317 
with  acromegaly,  273 
with  acute  pancreatitis,  252 
with  arterial  sclerosis,  271 
with    atrophy   of   the   pan- 
creas, 253 
with  carcinoma,  252,  256 
with    chronic    pancreatitis, 

256 
with  cirrhosis,  271 
with    exophthalmic    goitre, 

277 
with  functional  insufficiency 

of  the  pancreas,  269 
with    gangrenous    pancrea- 
titis, 252 
with  haemochromatosis,  301 
with     interacinar    pancrea- 
titis, 259 
with    interlobular    pancrea- 
titis, 259 
with  lesions  of  the  central 

nervous  system,  274 
with  nephritis,  275 
without    pancreatic    lesion, 

270 
with  pancreatic  calculi,  256 
with  tuberculosis,  204 
Digestive     disturbances,     after     re- 
moval of  pancreas,  311 
with  pancreatic  disease,  313 


INDEX. 


357 


Diverticula  of  the   intestine,  beside 
pancreatic  ducts,  64 
with     accessory     pancreas, 
47,  62 
Diverticulum  of  Vater,  39 
Duct  of  Santorini,  19 
papilla  of,  41 
patency  of,  42 
of  Wirsung,  19 

within  bile  papilla,  45 
Ducts    of    the    pancreas,    in    lower 
animals,  20 
regeneration  of,  59 
relation  of  parenchyma  to,  33 
variations  of,  26 
Duodenal    stricture,    with    chronic 
pancreatitis,  197 

Embryology.     See  Development. 
Exophthalmic  goitre,  with  diabetes, 
277 

Fat  necrosis,  clinical  significance  of, 

319 
disseminated,  135 
etiology  of,  138,  147,  153 
experimental,  139,  144 
histology  of,   137 
in  lower  animals,  137 
parapancreatic,  135,  158 
with  cholelithiasis,  155 
with    chronic    pancreatitis, 

137,  149,  154,  156 
with   duct-obstruction,    147, 

154 

with  hemorrhagic  pancrea- 
titis, 158 

with      pancreatic      hemor- 
rhage, 94 
Fat-splitting  ferment,  143,  147 

in  urine,  322 

Gall-stones.     See  Cholelithiasis. 
Gangrenous  pancreatitis,  91 


Gangrenous  pancreatitis,  pathogene- 
sis of,  131 

symptoms  of,  134,  325 

treatment  of,  328 

with  diabetes,  252,  309,  326 
Gastritis,  with  chronic  pancreatitis, 

193 

Glucose  in  blood,  236 

Glycogen,  237 

Glycolj^ic,  ferment,  245 

Glycosuria,  alimentary,  338 
with  acromegaly,  273 
with  adrenalin  injections,  277 
with  asphyxiation,  240 
with  exophthalmic  goitre,  277 
with  lesions  of  kidney,  276 
with  lesions  of  the  nervous  sys- 
tem, 239,  274 
with  partial  extirpation  of  the 

pancreas,  242 
with  phloridzin  poisoning,  240 

Hsemochromatosis,  280 

chronic  interacinar  pancreatitis 
with,  180 
pancreatitis  with,  288,  298 
cirrhosis  with,  287 
etiology  of,  295 
with  diabetes,  301 
Hsemofuscin,  282 
Hasmosiderin,  282 

Hemorrhage    in    the    pancreas,    92, 
130 
relation     of,     to     hemorrhagic 

pancreatitis,  130 
with  self-digestion  of  the  pan- 
creas, 160 
Hemorrhagic  pancreatitis,  90 
etiology  of,  98,  113 
experimental,  96,  121 
histology  of,   127 
pathogenesis  of,  127 
relation  of  gangrenous  pan- 
creatitis to,  131 


358 


INDEX. 


Hemorrhagic    pancreatitis,    relation 
of  pancreatic  hemorrhage 
to,  94,  130 
symptoms  of,  133,  323 
treatment  of,  327 
with  cholelithiasis,  100,  125 
with  diabetes,  309,  326 
Histology  of  the  pancreas,  67 
Hyaline  capillary  thrombosis,   128 
degeneration    of    the    pancreas, 
214 
affecting      islands      of 

Langerhans,  219 
etiology  of,  228 
with  diabetes,  262,  265 
with    interacinar    pan- 
creatitis, 211.  229 

Interacinar  islands,  68 
pancreatitis,  180 

etiology  of,  211,  213 
symptoms  of,  333 
with  diabetes,  259,  262 
Interalveolar  cell-islets,  68 
Interlobular  fissure,  36 
pancreatitis,  173 
etiology  of,  213 
symptoms  of,  332 
with  diabetes,  259,  262 
Islands  of  Langerhans,  68 

comparative    histology    of, 

69 
development  of,  76 
diminution    in    number    of, 

266 
distribution  of,  79 
fat  in  cells  of,  79,  214 
hyaline      degeneration     of, 

218 
in  accessory  pancreas,  56 
physiology  of,  81 
relation  of,  to  acini,  79,  81 
relation  of,  to  carbohydrate 
metabolism,  87 


Islands  of  Langerhans,  relation  of, 
to  diabetes  mellitus,  262 

relation  of,  to  lobule,  71 

structure  of,  74 

with  chronic  interstitial 
pancreatitis,  164 

with  congenital  syphilitic 
pancreatitis,  168 

with  haemochromatosis,  289, 
302 

with  interacinar  pancrea- 
titis, 179 

with  interlobular  pancrea- 
titis, 174,  177 

Levulose,  246 

Lobes  of  the  pancreas,  36 

Lobule  of  the  pancreas,  33,  70 

Meckel's   diverticulum,   with  acces- 
sory pancreas,  63 
Medulla,  lesions  of,  with  diabetes, 

275 
Morbus  maculosus  Werlhofii,  284 

Nephritis  with  diabetes,  275 

Obstruction  of  the  pancreatic  ducts, 
causing  interlobular 
pancreatitis,   173,   185 

disturbances  of  diges- 
tion with,  313 

fat  necrosis   with,   147, 

154 
parapancreatic    fat    ne- 
crosis with,  161 

Pancreas,    historical    data   concern- 
ing, 18 
extirpation  of,  241,  312 
parvum  of  Winslow,  46 
Pancreatic    diabetes,    experimental, 
241 
in  man,  246 


IXDEX. 


359 


Pancreatic  diabetes,  statistics  of,  248 
symptoms  of,  308 
juice,  production  of  fat  necro- 
sis by,  151 
Peri-pancreatic  abscess,  91 
symptoms  of,  325 
treatment  of,  329 
Pernicious  anaemia,  284 
Phloridzin,  240 
Pilocarpin,  81,  84,   149 
Primary  lobule  of  the  pancreas,  34, 

70 
Pseudo-follicles,  68 

Renal  diabetes,  275 

Secondary  cell-groups,  68 

lobule  of  the  pancreas,  34 
Self-digestion  of  the  pancreas,  159 
relation  to  pancreatic  hem- 
orrhage, 94 
Steatorrhoea,  314 

with    hemorrhagic    pancreatitis, 
326 
Suppurative  pancreatitis,  91 


Suppurative  pancreatitis,  fat  necro- 
sis with,  137 
relation   of,   to   gangrenous 

pancreatitis,  132 
symptoms  of,  325 
Symptoms  of  pancreatic  disease,  306 

obscurity  of,  304 
Syphilis,   with   chronic  pancreatitis, 

204 
Syphilitic  pancreatitis,  204 
congenital,  164 

Tertiary  lobule  of  the  pancreas,  34 
Thyroid  gland,  277 
Toluylendiamin,  297 
Traumatic  diabetes,  275 
Treatment  of  pancreatic  disease,  316 
with      pancreatic      ex- 
tracts, 317 
Tuberculosis,  with  chronic  pancrea- 
titis, 202 
with  diabetes,  204 

Vomiting,  causing  chronic  pancrea- 
titis, 193 


THE    END. 


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